AU2019262142B2 - RIP1 inhibitory compounds and methods for making and using the same - Google Patents

Abstract

Disclosed herein are kinase inhibitory compounds, such as a receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and/or combinations may be used to inhibit a RIP1 kinase

Description

RIP1 INHIBITORY COMPOUNDS AND METHODS FOR MAKING AND USING THESAME

CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of the earlier filing date of U.S. Provisional Application No. 62/666,452, filed on May 3, 2018, the entirety of which is incorporated herein by reference.

FIELD The present disclosure concerns compounds and methods of making and using the compounds, such as for inhibiting receptor-interacting protein-I kinase ("RIP1"), and for treating diseases and/or conditions related to RIP1.

BACKGROUND Receptor-interacting protein- kinase (referred to herein as "RIP1") belongs to the tyrosine kinase-like family and is a serine/threonine protein kinase involved in innate immune signaling. RIPI plays a central role in regulating cell signaling and its role in programmed cell death has been linked to various inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and/or conditions associated with inflammation and/or necroptotic cell death.

SUMMARY A first aspect of the invention provides for a compound, having a formula

O3 L R) (R1,aN 0

or a pharmaceutically acceptable salt thereof, wherein: ring B is 5-membered heteroaryl; L is a Ciioaliphatic linker; R 1 is Ra or Rb wherein at least one R1 is an R that is -NRdRd wherein the two Rd groups together with the nitrogen bound thereto provide a non-aromatic C3loheterocyclic group that is optionally substituted with one or more R' and/or R9 groups, in which R9 is halogen, -C1 .ioaliphatic-C-ioaromatic, or =0; la each of R2 and R3 independently are Ra; each R4 and each Ri ndependently are Ra or Rb; R' is independently for each occurrence H, D, C1ioaliphatic, or Ci-iocycloaliphatic; Rbis independently, for each occurrence except for that of the said at least one R', halogen or -NRdRd wherein (i) each Rd independently is R or Re; or (ii) two Rd groups together with the nitrogen bound thereto provide a C3.ioheterocyclic group; R° is independently for each occurrence -ORa, -NRa, C16alkyl, C16haloalkyl, C 1

. 6heteroalkyl, C3.cycloalkyl, or two R° groups join together to provide a C3loheterocyclic group with the Rb group to which the two R' groups are bound; m is 1 to 4; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4, or 5.

A second aspect of the invention provides for a pharmaceutical composition, comprising a compound according to the first aspect of the invention and an excipient, a therapeutic agent, an adjuvant, or combinations thereof.

A third aspect of the invention provides for a method, comprising contacting a receptor-interacting protein- (RIPI) kinase with a compound according to the first aspect of the invention, or the pharmaceutical composition according to the second aspect of the invention.

A fourth aspect of the invention provides for a method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of the compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof; or (ii) a therapeutically effective amount of a pharmaceutical composition according to the second aspect of the invention; wherein the subject has, or is suspected of having or developing, the disease, wherein the disease is a disease involving a receptor-interacting protein-i (RIP1) kinase.

lb

A fifth aspect of the invention provides for a method for making the compound according to the first aspect of the invention, comprising: coupling a starting material having a Formula A with an R-containing reagent having a formula R1 -H, by combining the starting material and the RI-containing reagent with a transition metal catalyst, a ligand component, and a solvent to form an Rl functionalized product; deprotecting an amine group of the R-functionalized product to provide an amine compound; and forming an amide bond between the amine compound and an acid-containing coupling partner; wherein Formula A is

0 I NHPG (m N X 2

Formula A;

the R1 -functionalized product has a structure satisfying Formula B

0 I NHPG ( N R 12 O

Formula B;

and the acid-containing coupling partner has a structure satisfying Formula C

q L H H0 (R4n RS

Formula C;

and wherein X is a halogen or a triflate; PG is an amine protecting group; and each of ring B, L, R, R2, R4, R, m, n, and p are as recited according to the first aspect of the invention.

ic

Disclosed herein are compound embodiments having a Formula I

(R1)m L a R"

R2 Formula I,

or a pharmaceutically acceptable salt thereof. A person of ordinary skill in the art will appreciate that compounds within the scope of Formula I also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and/or prodrugs thereof.

With reference to Formula I, ring Bis 5-membered heteroaryl; Lis a C-ioaliphatic linker; R 1 is Ra or Rb wherein at least one R1 is Rb; each of R2 and R3 independently are Ra; each R4 and each R 5 independently are Ra or R; Ra is independently for each occurrence H, D, C1-ioaliphatic, or CI-iocycloaliphatic; Rb is independently for each occurrence halogen or -NRdRd wherein (i) each Rd independently is Ra or Re; or (ii) two Rd groups together with the nitrogen bound thereto provide a C3-ioheterocyclic group; Re is independently for each occurrence -ORa, -NRa, CI-6alkyl, Ci-6haloalkyl, Ci-6heteroalkyl, C3-6cycloalkyl, or two Re groups join together to provide a C3-ioheterocyclic group with the Rb group to which the two Re groups are bound; m is I to 4, such as 1, 2, 3, or 4, with particular embodiments being 1 or 2; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4, or 5. Disclosed compounds may have a structure satisfying the formula below 0 0 B 4)N.(14 R1 N R 2 0

In any or all of the above embodiments, ring B can have a structure satisfying a formula

W W W

wherein at least one W is nitrogen, and each remaining W independently is selected from carbon, CH, oxygen, sulfur, nitrogen, or NH, with particular ring B embodiments being a triazole or an oxazole. Suitable exemplary triazoles include any of the following: N

HNN .- N N/; N

N NNN ?$-:,NtN:Nt "-Nt -N N ;or N

Suitable exemplary oxazoles include any of the following:

N &NN r

'-N ; ; J ON or O

Certain disclosed compounds comprise an R g roup that is an Ra group, wherein Ra is C1

C4 aliphatic, or that is an R group, wherein Rb is halogen, R 2 is Ra wherein Ra is C1 -C 4aliphatic, and R is Ra, 3

wherein Ra is hydrogen.

R 1 is Rb wherein Rb is -NRdRd wherein two Rd groups together with the nitrogen bound thereto provide a C 3 -ioheterocyclic group. In some embodiments, C 3-ioheterocyclic group is substituted with one or

more Re groups and/or has one or more additional heteroatoms in addition to the nitrogen to which both Rd groups are bound in certain embodiments. In some embodiments, the C 3-ioheterocyclic group is substituted

with two R° groups thatjoin together to provide a C 3-ioheterocyclic group and this C 3-ioheterocyclic, along with the Rb group can provide a spirocyclic group or a bicyclic group. Certain disclosed spirocyclic groups

comprise at least two rings, with each ring having a different number of atoms in the ring. In some embodiments, the spirocyclic group comprises at least two rings, wherein a first ring and a second ring of the spirocyclic group have a different number of carbon atoms, a different number of heteroatoms, or both. In

yet additional embodiments, each ring of the spirocyclic group comprises a heteroatom in the ring, and each ring of the spirocyclic group may have a different heteroatom in the ring or the same heteroatom in the ring, such as at least one oxygen atom and at least one nitrogen atom. In some embodiments, the spirocyclic group comprises a first ring comprising a nitrogen atom and a second ring comprising an oxygen atom. The spirocyclic group comprises a first ring coupled to the ring A phenyl group, wherein the first ring has from 3 to 7 atoms and a second ring has from 3 to 7 atoms. Typically, the spirocyclic group comprises greater than

7 total atoms in the spirocyclic system, with some embodiments having a spirocyclic group that comprises 9

total atoms in the spirocyclic system. The C 3-1oheterocyclic formed by the two R° groups and the C 3 -ioheterocyclic formed by the two Rd groups of Rb may provide a bicyclic group, such as a bicyclic group comprising two or more heteroatoms in

the bicyclic group, such as nitrogen and/or oxygen. The bicyclic group may be attached to the ring A phenyl group through a nitrogen atom of the bicyclic group. In some embodiments, the bicyclic group may be a

fused bicyclic group or a bridged bicyclic group. In any or all of the above embodiments, R1 is selected from

HO NN

0 0

N Nr N0 OQjN

O\NX +Nc O R 6-N KN+ N

Nn ~ (F)n Nk N

zN'R

VN N -N NR RR6 \ 6 N N

N

N(Re)R N -R N R(

N R N J 0- (NR6F)n

N NON R N r N

; or H i wherein each n independently is an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; and R ndependently

is selected from hydrogen; aliphatic, such as C.ioaliphatic; aromatic, such as C5-ioaromatic; or heteroaliphatic, such as Ciioheteroaliphatic. Exemplary compound embodiments are disclosed herein and can be selected from any one or more of compounds I-1 through 1-27.

Also disclosed herein are pharmaceutical composition embodiments comprising a compound (or compounds) according to any of the formulas and/or species disclosed herein (or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug

thereof), and at least one additional active and/or non-active agent, such as an excipient, a therapeutic agent, an adjuvant, or combinations thereof.

Also disclosed herein are embodiments of a method for using disclosed compounds. One such

embodiment comprises contacting a receptor-interacting protein-i (RIP1) kinase with a compound according to any of the formulas and/or species disclosed herein (or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof), or a pharmaceutical

composition embodiment described herein. Contacting can occur ex vivo or in vivo. Also disclosed is a method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of the compound according to any of the formulas and/or

species disclosed herein (or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof); and/or (ii) a therapeutically effective amount of a

pharmaceutical composition embodiment described herein; wherein the subject has, or is suspected of having or developing a disease involving a receptor-interacting protein-i (RIPi) kinase. The foregoing and other objects, features, and advantages of the present disclosure will become more apparent from the following detailed description.

DETAILED DESCRIPTION I. Overview of Terms

The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. The

singular forms "a," "'an,"and "the" refer to one or more than one, unless the context clearly dictates

otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B," means "including A, B, or A and B," without excluding additional

elements. All references, including patents and patent applications cited herein, are incorporated by reference.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights,

percentages, temperatures, times, and so forth, as used in the specification or claims are to be understood as being modified by the term "about." Accordingly, unless otherwise indicated, implicitly or explicitly, the numerical parameters set forth are approximations that may depend on the desired properties sought and/or

limits of detection under standard test conditions/methods. When directly and explicitly distinguishing

embodiments from discussed prior art, the embodiment numbers are not approximates unless the word "about" is expressly recited. Unless explained otherwise, all technical and scientific terms used herein have the same meaning as

commonly understood to one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the

present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. When chemical structures are depicted or described, unless explicitly stated otherwise, all carbons

are assumed to include hydrogen so that each carbon conforms to a valence of four. For example, in the

structure on the left-hand side of the schematic below there are nine hydrogen atoms implied. The nine hydrogen atoms are depicted in the right-hand structure. H H H

Br Br

H H 4H H H

Sometimes a particular atom in a structure is described in textual formula as having a hydrogen or hydrogen atoms, for example -CH 2CH 2-. It will be understood by a person of ordinary skill in the art that

the aforementioned descriptive techniques are common in the chemical arts to provide brevity and simplicity

to description of organic structures. If an R group is depicted as "floating" on a ring system, as for example with R' in the group: 0 (R1 q

F2 0 then, unless otherwise defined, a substituent R (e.g., R above) can reside on any atom of the fused bicyclic

ring system, excluding the atom carrying the bond with the "~"symbol, so long as a stable structure is formed.

When a group R is depicted as existing on a ring system containing saturated carbons, as for example in the formula:

-(R)y

where, in this example, y can be more than one, assuming each replaces a currently depicted, implied, or

expressly defined hydrogen on the ring; then, unless otherwise defined, two R's can reside on the same carbon. A simple example is when R is a methyl group. The depicted structure can exist as a geminal dimethyl on a carbon of the depicted ring (an "annular" carbon). In another example, two R's on the same carbon, including that same carbon, can be included in a ring, thus creating a spirocyclic ring (a "spirocyclyl" group) structure. For example, as shown below two Rs can form an oxetane or tetrahydropyran ring in a spirocyclic arrangement with the piperidine or azetidine ring, as

-4-N O or -- N 1I/O

As used herein, the term "substituted" refers to all subsequent modifiers in a term, for example in the term "substituted arylC1.8alkyl," substitution may occur on the "Cl8alkyl" portion, the "aryl" portion or both portions of the arylC1.8alkyl group.

"Substituted," when used to modify a specified group or moiety, means that at least one, and perhaps two or more, hydrogen atoms of the specified group or moiety is independently replaced with the same or different substituent groups as defined below. In a particular embodiment, a group, moiety or

substituent may be substituted or unsubstituted, unless expressly defined as either "unsubstituted" or "substituted." Accordingly, any of the groups specified herein may be unsubstituted or substituted unless

the context indicates otherwise or a particular structural formula precludes substitution. In particular

embodiments, a substituent may or may not be expressly defined as substituted, but is still contemplated to be optionally substituted. For example, an "aliphatic" or a "cyclic" moiety may be unsubstituted or substituted, but an "unsubstituted aliphatic" or an "unsubstituted cyclic" is not substituted.

"Substituents" or "substituent groups" for substituting for one or more hydrogen atoms on saturated carbon atoms in the specified group or moiety can be, unless otherwise specified, -R6 0, halo, =0, -OR7 4, -SR?°, -N(R 80)2, haloalkyl, perhaloalkyl, -CN, -NO 2, =N 2, -N 3 , -S0 2R°, -SO3-M+, -S0 3R°, -OS0 2 R7 °, 70 2 -OSO3-M*, -OS0 3R , -P(O)(O-)2(M*) 2 , -P(O)(O-)2M +, -P(O)(OR 74)O-M+, 7 -P(O)(OR 0) 2 , -C(O)R 70 ,

70 70 -C(S)R , -C(NR )R , -CO2-M+, -C0 2R ,-C(S)OR 07 , -C(O)N(R 80)2, -C(NR7 0)(R 80)2 , -OC(O)R70 70 70 ,

-OC(S)R 70, -OCO2-M*, -OC0 2 R07 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2M+, -NR 70 C02 R7 0 ,

-NR 7 0C(S)OR 70 , -NR70C(O)N(R 80)2, -NR 70C(NR 7 4)R 7 0 and -NR 70C(NR7 4)N(R 80)2, where R 60 is Ciioaliphatic, heteroaliphatic, or cycloaliphatic, typically, C16aliphatic, more typically C1-6alkyl, where R6 0 optionally may be substituted; each R 70 is independently for each occurrence hydrogen or R6 0 ; each R80 is independently for

each occurrence R 7 0 or alternatively, two R 80groups, taken together with the nitrogen atom to which they are bonded, form a 3- to 7-membered heterocycloaliphatic, which optionally includes from 1 to 4 of the same or different additional heteroatoms selected from 0, N and S, of which N optionally has R 70 substitution, such

as H or C1 -C 3 alkyl substitution; and each M+ is a counter ion with a net single positive charge. Each M+ is independently for each occurrence, for example, an alkali metal ion, such as K+, Na+, Li+; an ammonium ion,

such as *N(R60) 4 ; a protonated amino acid ion, such as a lysine ion, or an arginine ion; or an alkaline metal

earth ion, such as [Ca2+]o. 5, [Mg 2+]o.5, or [Ba2+]o.5(a subscript "0.5"means, for example, that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound can serve as the counter ion for such divalent alkali earth ions). As specific examples, -N(R' 0 )2 includes -NH 2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl and the like. Any two hydrogen atoms on a single carbon also can be replaced with, for example, =0, =NR4, =N-OR7 4, =N 2 or =S.

Substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbons are, unless otherwise specified, -R6 0 , halo, -O-M*,-OR 7 4, -SR7 4, -S-M*, -N(R' 0) 2

, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -SO 2R°, -SO3-M*, -SO 3R°, -OSO 2 R0 , -OSO3-M*, -OSO 3 R 7 , -PO3-2(M*) 2 , -PO3-2 M 2 *, -P(O)(OR4)O-M*, -P(O)(OR7 0 ) 2, -C(O)R4, -C(S)R4, -C(NR70 )R70

, -CO2M*, -CO 2 R 70 , -C(S)OR 70 , -C(O)NR'0 R80 , -C(NR 74)N(R0) 2, -OC(O)R 70 , -OC(S)R 70 , -OCO2 -M, -OCO 2 R 70, -OC(S)OR70 , -NR 70 C(O)R 70 , -NR70 C(S)R 70 , -NR 70 CO2 -M, -NR70 CO 2 R 70 , -NR70 C(S)OR 70

, -NR 70C(O)N(R' 0) 2 , -NR 7 0C(NR7 4)R 7 0and -NR 7 0C(NR 7 4)N(R%0) 2, where R 60, R 7 0, R'0 and M* are as previously defined. In an independent embodiment, the substituents are not -O-M*, -OR 70 , -SR 70 , or -S-M*. Substituent groups for replacing hydrogen atoms on nitrogen atoms in groups containing such 60 nitrogen atoms are, unless otherwise specified, -R ,-O-M*, -OR07 , -SR 70 , -S-M*, -N(R' 0) 2, perhaloalkyl, 07 2 2 -CN, -NO, -NO 2 , -S(O) 2R 70 , -SO3-M*, -S 3R 70 , -OS() 2R 70 , -OSO3-M*, -OS 3R , -PO 3 -(M*) 2 , -PO 3 -M2 +, -P(O)(OR 70)O-M*, -P(O)(OR 70 )(OR 70), -C(O)R70 , -C(S)R70 , -C(NR 70 )R70 , -C0 2R 70 , -C(S)OR 70

, -C(O)NR' 0R8 0, -C(NR 70)NR'R'°, -OC(O)R7 0, -OC(S)R 70, -OCO 2 R 70 , -OC(S)OR07 , -NR70 C(O)R 70

, -NR 70C(S)R 70, -NR70CO 2R 70 , -NR70C(S)OR 70 , -NR70 C(O)N(R' 0) 2 , -NR 70 C(NR 74)R 70 and -NR 7 0C(NR 7 0)N(R%0) 2 , where R 60, R 7 , R'0 and M* are as previously defined.

In one embodiment, a group that is substituted has at least one substituent up to the number of substituents possible for a particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

Additionally, in embodiments where a group or moiety is substituted with a substituted substituent,

the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Thus, in a group or moiety comprising a first group that is a substituent on a second group that is itself a substituent on a third group, which is attached to the parent structure, the first (outermost) group can only be

substituted with unsubstituted substituents. For example, in a group comprising -(aryl-)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are not themselves substituted.

Any group or moiety defined herein can be connected to any other portion of a disclosed structure, such as a parent or core structure, as would be understood by a person of ordinary skill in the art, such as by considering valence rules, comparison to exemplary species, and/or considering functionality, unless the

connectivity of the group or moiety to the other portion of the structure is expressly stated, or is implied by

context. "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, or aromatic (including

both aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl,

C(O)C 1 -C 6alkyl, -C(O)C 1-Chaloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl,

C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include, -C(O)H, -C(O)Me, -C(O)Et, or

C(O)cyclopropyl. "Aliphatic" refers to a substantially hydrocarbon-based group or moiety. An aliphatic group or moiety can be acyclic, including alkyl, alkenyl, or alkynyl groups (as well as alkylene, alkenylene, or

alkynylene groups), cyclic versions thereof, such as cycloaliphatic groups or moieties including cycloalkyl,

cycloalkenyl or cycloalkynyl, and further including straight- and branched-chain arrangements, and all stereo and position isomers as well. Unless expressly stated otherwise, an aliphatic group contains from one to twenty-five carbon atoms (CI-25 ); for example, from one to fifteen (C15), from one to ten (C1.1o) from one

to six (C1.6), or from one to four carbon atoms (C 14 ) for an acyclic aliphatic group or moiety, or from three to fifteen (C 3 _1 5 ) from three to ten (C 3 -10), from three tosix (C 3 -6), or from three to four (C 3 -4 ) carbon atoms

for a cycloaliphatic group or moiety. An aliphatic group may be substituted or unsubstituted, unless expressly referred to as an "unsubstituted aliphatic" or a "substituted aliphatic." An aliphatic group can be substituted with one or more substituents (up to two substituents for each methylene carbon in an aliphatic

chain, or up to one substituent for each carbon of a -C=C- double bond in an aliphatic chain, or up to one

substituent for a carbon of a terminal methine group). "Lower aliphatic" refers to an aliphatic group containing from one to ten carbon atoms (C1.o), such as from one to six (C1 .6 ), or from one to four (C1 .4 ) carbon atoms; or from three to ten (C 3 -10), such as from

three to six (C 3 -6 ) carbon atoms for a lower cycloaliphatic group. "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl or a substituted or

unsubstituted cycloalkyl group. In certain examples R is a C1.6 alkyl group or a C3-cycloalkyl group. Methoxy (-OCH 3) and ethoxy (-OCH 2CH 3) are exemplary alkoxy groups. In a substituted alkoxy, R is substituted alkyl or substituted cycloalkyl, examples of which in the presently disclosed compounds include

haloalkoxy groups, such as -OCF 2 H.

"Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH 2 CH2 -O-CH2CH 3 is an exemplary alkoxyalkyl group. "Alkyl" refers to a saturated aliphatic hydrocarbyl group having from 1 to at least 25 (C- 25 ) carbon

atoms, more typically I to 10 (C1.10) carbon atoms such as I to 6 (C- 6 ) carbon atoms. An alkyl moiety may be substituted or unsubstituted. This term includes, by way of example, linear and branched hydrocarbyl

groups such as methyl (CH 3 ), ethyl (-CH 2 CH3), n-propyl (-CH 2 CH2CH 3), isopropyl (-CH(CH 3)2 ), n-butyl(

CH2 CH2CH 2CH3 ), isobutyl (-CH 2CH2 (CH3 )2 ), sec-butyl (-CH(CH 3)(CH 2 CH3), t-butyl (-C(CH 3) 3), n-pentyl (-CH 2CH 2CH 2CH2 CH3), and neopentyl (-CH 2 C(CH3)3). "Amino" refers to the group -NH 2, -NHR, or -NRR, where each R independently is selected from H,

aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heterocycloaliphatic, or two R groups together with the nitrogen attached thereto form a heterocyclic ring. Examples of such heterocyclic rings include those wherein two R groups together with the nitrogen to which they are attached form a

(CH 2)2 -5- ring optionally interrupted by one or two heteroatom groups, such as -0- or -N(Rg) such as in the

-+N O - -N N-R 60 groups \--/ and \--/ wherein R9 is R7 °, -C(O)R°, -C(O)OR° or -C(O)N(R0)2. "Amide" refers to the group -N(R)acyl, wherein R is hydrogen, heteroaliphatic, or aliphatic, such as

alkyl, particularly C1.6alkyl.

"Aromatic" refers to a cyclic, conjugated group or moiety of, unless specified otherwise, from 5 to 15 ring atoms having a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple condensed rings in

which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), that is at least one ring, and optionally multiple condensed rings, have a continuous, delocalized R-electron system. Typically, the

number of out of plane R-electrons corresponds to the Hickel rule (4n + 2). The point of attachment to the parent structure typically is through an aromatic portion of the condensed ring system. For example,

O

o . However, in certain examples, context or express disclosure may indicate that the point of

attachment is through a non-aromatic portion of the condensed ring system. For example, '^"'

An aromatic group or moiety may comprise only carbon atoms in the ring, such as in an aryl group or moiety, or it may comprise one or more ring carbon atoms and one or more ring heteroatoms comprising a

lone pair of electrons (e.g. S, 0, N, P, or Si), such as in a heteroaryl group or moiety. Unless otherwise stated, an aromatic group may be substituted or unsubstituted. "Aryl" refers to an aromatic carbocyclic group of, unless specified otherwise, from 6 to 15 carbon

atoms having a single ring (e.g., phenyl) or multiple condensed rings in which at least one ring is aromatic

(e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, and the like). If any aromatic ring portion contains a heteroatom, the group is heteroaryl and not aryl. Aryl groups may be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise stated, an aryl group may be substituted or unsubstituted.

"Araliphatic"refers to an aryl group attached to the parent via an aliphatic moiety. Araliphatic includes aralkyl or arylalkyl groups such as benzyl and phenylethyl. "Carboxyl" refers to -CO 2H. "Carboxamide" refers to -C(O)amino.

"Carboxyl ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic,

heteroaliphatic, or aromatic (including both aryl and heteroaryl).

"Carboxylate" refers to -C(O)0- or salts thereof. "Cyano" refers to the group -CN.

"Cycloaliphatic" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl), or multiple rings, such as in a fused, bridged or spirocyclic system, the ring or at least one of the rings in the system is aliphatic. Typically, the point of attachment to the parent structure is through an aliphatic portion of the multiple ring system. Cycloaliphatic includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl and cycloalkynyl. A cycloaliphatic group may contain from three to twenty-five carbon atoms; for example, from three to fifteen, from three to ten, or from three to six carbon atoms. Unless otherwise stated, a cycloaliphatic group may be substituted or unsubstituted. Exemplary cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

"Halo," "halide" or "halogen" refers to fluoro, chloro, bromo or iodo. "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH 2 F, -CHF2 and -CF3 . "Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., at least one carbon atom from an aliphatic compound or group comprising at

least two carbon atoms, has been replaced with an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups may be substituted or unsubstituted, branched or unbranched, chiral or achiral, and/or acyclic or cyclic, such as a

heterocycloaliphatic group.

"Heteroaryl" refers to an aromatic group or moiety having, unless specified otherwise, from 5 to 15 ring atoms comprising at least one carbon atom and at least one heteroatom, such as N, S, 0, P, or Si. A heteroaryl group or moiety may comprise a single ring (e.g., pyridinyl, pyrimidinyl or pyrazolyl) or multiple

condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). Heteroaryl groups or moiety may be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise stated, a heteroaryl group or

moiety may be substituted or unsubstituted. "Heterocyclyl," "heterocyclo" and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically refer to a stable three- to fifteen-membered ring moiety comprising at least

one carbon atom, and typically plural carbon atoms, and at least one, such as from one to five, heteroatoms.

The heteroatom(s) may be nitrogen, phosphorus, oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be a monocyclic moiety, or may comprise multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such a multiple ring moiety can include fused

or bridged ring systems as well as spirocyclic systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moiety can be optionally oxidized to various oxidation states. For

convenience, nitrogens, particularly, but not exclusively, those defined as annular aromatic nitrogens, are meant to include their corresponding N-oxide form, although not explicitly defined as such in a particular example. Thus, for a compound having, for example, a pyridinyl ring, the corresponding pyridinyl-N-oxide

is included as another compound of the invention, unless expressly excluded or excluded by context. In

addition, annular nitrogen atoms can be optionally quaternized. Heterocycle includes heteroaryl moieties, and heteroalicyclyl or heterocycloaliphatic moieties, which are heterocyclyl rings that are partially or fully saturated. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2 oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

"Hydroxyl" refers to the group -OH. "Nitro" refers to the group -NO 2 .

"Phosphate" refers to the group -O-P(O)(OR') 2, where each -OR' independently is -OH; -0

aliphatic, such as -0-alkyl or -- cycloalkyl; -0-aromatic, including both -0-aryl and -0-heteroaryl; -0

aralkyl; or -OR' is -O-M', where M' is a counter ion with a single positive charge. Each M' may be an alkali ion, such as K+, Na, Li; an ammonium ion, such as 'N(R") 4 where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth ion, such as [Ca2+]o. 5, [Mg 2+]. 5 ,or

[Ba2+]o..5 Phosphonooxyalkyl refers to the group -alkyl-phosphate, such as, for example, -CH OP(O)(OH) 2 2

, or a salt thereof, such as -CH2OP(O)(O-Na+) 2, and (((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl

ester of a phosphonooxyalkyl group, such as, for example, -CHOP(O)(O-tert-butyl) 2 2 .

"Phosphonate" refers to the group -P(O)(OR') 2, where each -OR' independently is -OH; -0 aliphatic such as -0-alkyl or -0-cycloalkyl; -0-aromatic, including both -0-aryl and -0-heteroaryl; or -0

aralkyl; or -OR' is -O-M+, and M+ is a counter ion with a single positive charge. Each M+ is a positively

charged counterion and may be, by way of example, an alkali metal ion, such as K+, Na+, Li+; an ammonium ion, such as *N(R")4 where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth metal ion, such as [Ca2+]o. 5, [Mg 2+]o. 5 , or [Ba2+]o. 5. Phosphonoalkyl refers to

the group -alkyl-phosphonate, such as, for example, -CH 2P(O)(OH) 2 , or -CH 2P(O)(O-Na+) 2, and ((dialkoxyphosphoryl)alkyl) refers to the dialkyl ester of a phosphonoalkyl group, such as, for example,

-CH 2P(O)(O-tert-butyl) 2 .

"Patient" or "Subject" may refer generally to any living being, but more typically refers to mammals and other animals, particularly humans. Thus disclosed methods are applicable to both human

therapy and veterinary applications.

"Pharmaceutically acceptable excipient" refers to a substance, other than the active ingredient, that is included in a formulation of the active ingredient. As used herein, an excipient may be incorporated within particles of a pharmaceutical composition, or it may be physically mixed with particles of a

pharmaceutical composition. An excipient can be used, for example, to dilute an active agent and/or to modify properties of a pharmaceutical composition. Excipients can include, but are not limited to, antiadherents, binders, coatings, enteric coatings, disintegrants, flavorings, sweeteners, colorants, lubricants, glidants, sorbents, preservatives, carriers or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, saccharides and their derivatives such as disaccharides, polysaccharides and sugar alcohols, protein, synthetic polymers, crosslinked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethyleneglycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxy methyl cellulose, dipalmitoyl phosphatidyl choline (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulphite or lanolin. An "adjuvant" is a component that modifies the effect of other agents, typically the active ingredient. Adjuvants are often pharmacological and/or immunological agents. An adjuvant may modify the effect of an active ingredient by increasing an immune response. An adjuvant may also act as a stabilizing agent for a formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants, such as Freund's complete adjuvant or Freund's incomplete adjuvant. "Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspension aid, solubilizing aid, or aerosolization aid. Remington: The Science and Practiceof Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21' Edition (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents. In general, the nature of the carrier will depend on the particular mode of administration being employed. For instance, parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. In some examples, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (for example, by parenteral, intramuscular, or subcutaneous injection). In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound that are derived from a variety of organic and inorganic counter ions as will be known to a person of ordinary skill in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free bases while formed by acid partners. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzene sulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" that are derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19 which is incorporated herein by reference.) In particular disclosed embodiments, the compounds may be a formate, trifluoroactate, hydrochloride or sodium salt. "Effective amount" with respect to a compound or pharmaceutical composition refers to an amount of the compound or pharmaceutical composition sufficient to achieve a particular desired result, such as to inhibit a protein or enzyme. In particular embodiments, an "effective amount" is an amount sufficient to inhibit RIPi; to elicit a desired biological or medical response in a tissue, system, subject or patient; to treat a specified disorder or disease; to ameliorate or eradicate one or more of its symptoms; and/or to prevent the occurrence of the disease or disorder. The amount of a compound which constitutes an "effective amount" may vary depending on the compound, the desired result, the disease state and its severity, the size, age, and gender of the patient to be treated and the like, as will be understood by a person of ordinary skill in the art.

"Prodrug"refers to compounds that are transformed in vivo to yield a biologically active compound, or a compound more biologically active than the parent compound. In vivo transformation may occur, for example, by hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (for example C1.6alkyl esters ). Other prodrug moieties include phosphate esters, such as -CH2 -0 P(O)(OR') 2 or a salt thereof, wherein R'is H or C16 alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but notlimited to benzyl. Examples of pharmaceutically acceptable aides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons). Amides and esters of disclosed exemplary embodiments of compounds according to the present invention can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro drugs as Novel Delivery Systems," Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes. "Solvate" refers to a complex formed by combination of solvent molecules with molecules or ions of a solute. The solvent can be an organic solvent, an inorganic solvent, or amixture of both. Exemplary solvents include, but are not limited to, alcohols, such as methanol, ethanol, propanol; aides such as N,N dialiphatic aides, such as N,N-dimethylformamide; tetrahydrofuran; alkylsulfoxides, such as dimethylsulfoxide; water; and combinations thereof. The compounds described herein can exist in un solvated as well as solvated forms when combined with solvents, pharmaceutically acceptable or not, such as water, ethanol, and the like. Solvated forms of the presently disclosed compounds are within the scope of the embodiments disclosed herein.

"Sulfonamide" refers to the group or moiety -SO 2 amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl). "Sulfanyl" refers to the group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic, (including

both-S-aryl and -S-heteroaryl).

"Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, or S(O)aromatic (including both -S(O)aryl and -S(O)heteroaryl). "Sulfonyl" refers to the group: -S0 2H, -S 2 aliphatic, -SO 2heteroaliphatic,-SO 2 aromatic (including

both -SO2aryl and -SO 2heteroaryl). "Treating"or "treatment"as used herein concerns treatment of a disease or condition of interest in

a patient or subject, particularly a human having the disease or condition of interest, and includes by way of example, and without limitation:

(i) preventing the disease or condition from occurring in a patient or subject, in particular, when such patient or subject is predisposed to the condition but has not yet been diagnosed as having it;

(ii) inhibiting the disease or condition, for example, arresting or slowing its development; (iii) relieving the disease or condition, for example, causing diminution of a symptom or regression of the disease or condition or a symptom thereof; or

(iv) stabilizing the disease or condition.

As used herein, the terms "disease" and "condition" can be used interchangeably or can be different

in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been determined) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, where a more or less specific set of symptoms have been identified by clinicians.

The above definitions and the following general formulas are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution

patterns are easily recognized by a person having ordinary skill in the art. A person of ordinary skill in the art will appreciate that compounds may exhibit the phenomena of

tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For example, certain disclosed compounds can include one or more chiral centers and/or double bonds and as a

consequence can exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, diasteromers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds can exist in several tautomeric forms, including the enol form, the keto form, and mixtures

thereof. As the various compound names, formulae and compound drawings within the specification and

claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, a person of ordinary skill in the art will appreciate that the disclosed compounds encompass any tautomeric, conformational isomeric, optical isomeric, and/or geometric isomeric forms of

the compounds described herein, as well as mixtures of these various different isomeric forms. Mixtures of different isomeric forms, including mixtures of enantiomers and/or stereoisomers, can be separated to

provide each separate enantiomers and/or stereoisomer using techniques known to those of ordinary skill in the art, particularly with the benefit of the present disclosure. In cases oflimited rotation, e.g. around the amide bond or between two directly attached rings such as pyridinyl rings, biphenyl groups, and the like,

atropisomers are also possible and are also specifically included in the compounds of the invention.

In any embodiments, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, may be replaced by a deuterium or a tritium. Thus, a recitation of alkyl includes deuterated alkyl, where from one to the maximum number of hydrogens present may be replaced by

deuterium. For example, ethyl refers to both C 2H5 or C 2H 5 where from 1 to 5 hydrogens are replaced by deuterium, such as in C 2 DxH5 ,.

II. RIPi-Active Compounds and Pharmaceutical Compositions Comprising RIP-active Compounds A. Compounds Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that

are useful for inhibiting RIP1 and/or for treating diseases and/or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds are able to selectively inhibit RIPi over RIP2, RIP3, or both RIP2 and RIP3. In some embodiments, a compound of

the present disclosure can have a structure satisfying Formula I

)0 1 N OP (R )m A

1 2

Formula I, or a pharmaceutically acceptable salt thereof. A person of ordinary skill in the art will appreciate that the

disclosed general formulas include within their scope all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and/or prodrugs of compounds otherwise having structural features required by such formulas.

With reference to Formula I: ring B is 5-membered heteroaryl;

L is a Ciioaliphatic linker; R 1 is Ra or Rb wherein at least one R1 is Rb; each of R 2 and R3 independently are Ra;

each R 4 and each Ri ndependently are Ra or Rb;

Ra is independently for each occurrence H or D (except for embodiments where L and/or R is Ra), C1ioaliphatic, or C.iocycloaliphatic;

R is independently for each occurrence halogen or -NRdRd wherein (i) each Rd independently is Ra or Re; or (ii) two Rd groups together with the nitrogen bound thereto provide a C 3-ioheterocyclic group, with some embodiments providing a C 3-ioheterocyclic group that is substituted with one or

more R° and/or R9 groups and/or that has one or more additional heteroatoms in addition to the nitrogen to which both Rd groups are bound; R° is independently for each occurrence -ORa, NRa, C16alkyl, C16haloalkyl, C1 6 heteroalkyl, C 3

6Cycloalkyl, or two R° groups join together to provide a C 3 -ioheterocyclic group with the Rb group to which the two R° groups are bound, and in some embodiments, the C3-ioheterocyclic group is substituted with one or more R9 groups; R9 is halogen, C1 .ioaliphatic-C 5 _ 1 oaromatic, or =0;

m is I to 4, such as 1, 2, 3, or 4, with particular embodiments being 1 or 2; n is 0, 1 or 2; and

p is 0, 1, 2, 3, 4, or 5. In particular embodiments of Formula I, the 5-membered heteroaryl group can have a structure

vW

satisfying formula W wherein at least one W is nitrogen, and each remaining W independently is

selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered

heteroaryl group is a triazole or an oxazole. Exemplary triazoles include any of the following:

N HN'N .N ; N N N-- N

N ;t N ;or N

Exemplary oxazoles are include any of the following:

7N N N

or O

In particular embodiments of Formula I, L is a C1.ioaliphatic linker, such as a C1.C 4alkylene linker (e.g., -CH 2 -, -CH2CH 2-, -CH 2CH2CH2-, or -CH 2CH 2CH2CH2-). In some embodiments, L is -CH 2 -. R1 can be positioned on any suitable carbon atom(s) of phenyl ring A, such as at the 1, 2, 3, or 4 position, illustrated in Formula I. In some embodiments, one R is Ra, wherein Ra is C1.Cioalkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl), and a second R is Rb, wherein R is halogen (e.g., Br, F, I, or Cl) or -NRdRd wherein two Rd groups together with the nitrogen bound thereto provide a C 4 _ 9heterocyclic group. In some embodiments, the C 4 _9 heterocyclic group is substituted with one

or more R° groups and/or has one or more additional heteroatoms in addition to the nitrogen to which both Rd groups are bound. Some compound embodiments comprise at least one R 1 group that is an R group, wherein Rb is -NRdRd, wherein (i) each Rd independently is Ra or R; or (ii) two Rd groups together with the nitrogen bound thereto provide a C 4 _9 heterocyclic group. In some embodiments, R is -NRdRd, wherein one

Rdis R, wherein R is H, and the other Rd is R°, wherein R°is C 16 haloalkyl. In some embodiments, the

heterocyclic group comprises 1 or 2 heteroatoms (including the nitrogen atom of Rb). Certain heterocyclic

groups comprise the nitrogen atom of the Rb group and either an oxygen atom or an additional nitrogen atom. The heterocyclic groups in some compound embodiments are bound to the ring A phenyl ring of Formula I via the nitrogen atom of the R group. In some embodiments, the heterocyclic group is substituted

with two R°groups, wherein R°is independently for each occurrence C1 6 haloalkyl (e.g., -CH2 Cl) or C1.

6 heteroalkyl (e.g., CH2 OH). The heterocyclic groups are 6-membered or 7-membered heterocyclic groups.

In exemplary embodiments, the heterocyclic group is

HO N N /( \ R -NNY \_ ( F) ci , , /

wherein each n independently is an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; and R6 is selected

from hydrogen; aliphatic, such as C.ioaliphatic; aromatic, such as C5.oaromatic; or heteroaliphatic, such as Ciioheteroaliphatic. In some embodiments, R1 is R wherein Rb is -NRdRd and both Rd groups together with the nitrogen

bound thereto provide a C 4 _ 9heterocyclic group substituted with at least two R° groups wherein the two R° groups join together to provide a C 3-1 oheterocyclic group with the Rb group to which they are attached. In such embodiments, the two R° groups can join together such that a bicyclic group or a spirocyclic group is provided (wherein one ring of the bicyclic group or spirocyclic group is provided by the R group and the other ring of the bicylic group or the spirocyclic group is provided by the two R° groups). In embodiments comprising a spirocyclic group, each ring of the spirocyclic group may have the same number of atoms or a different number of atoms. In particular embodiments, the spirocyclic group comprises at least two rings, wherein a first ring and a second ring of the spirocyclic group have a different number of carbon atoms, a different number of heteroatoms, or both. In some embodiments, the two rings of the spirocyclic group comprise the same number of carbon atoms, the same number of heteroatoms, or both. In some embodiments, each ring of the spirocyclic group comprises a heteroatom in the ring and the heteroatom may be the same in each ring, or each ring of the spirocyclic group may have a different heteroatom in the ring.

The spirocyclic group can comprise a first ring coupled to a carbon atom of the ring A phenyl group, wherein the first ring has from 3 to 7 atoms, and a second ring has from 3 to 7 atoms. In some embodiments, the spirocyclic group comprises at least one oxygen atom in addition to the nitrogen atom of the R group.

The spirocyclic group may comprise greater than 7 total atoms in the spirocyclic system with particular

embodiments comprising 9 total atoms in the spirocyclic system. In exemplary embodiments, R together with two R° groups can provide the following spirocycles:

N R6-NX N+ OQ\/N±.

0 ~ 04

R NON O00NN 1o 0

wherein R 6 is selected from hydrogen; aliphatic, such as C.ioaliphatic; aromatic, such as C-ioaromatic; or heteroaliphatic, such as C1 1I oheteroaliphatic. A bicyclic group may be provided by the Rb group and the two R° groups attached thereto. The

bicyclic may group comprise two or more heteroatoms in the bicyclic group. In such embodiments, the two

or more heteroatoms are nitrogen and/or oxygen. In some embodiments, the bicyclic group is attached to a carbon atom of the ring A phenyl group illustrated in the general formulas provided herein through the nitrogen atom of the R group when Rb is -NRdRd. The bicyclic group can be any bicyclic group, including

fused bicyclic groups and bridged bicyclic groups, but for certain exemplary embodiments the bicyclic group is a 2.2.1 bicycle, a 3.2.1 bicycle, or a 3.2.2 bicycle. In exemplary embodiments when R together

with two R° groups provide a bicyclic group, the bicycle can be

N N N -_ N 18 N NR tN O N(R)R WN O DN+

N R R(6 N N N\N

N R N R6 N R

R N 'R N- N N (.-N NR N

N N(R)R or N - N'RN

6 wherein each n independently is an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; and R independently is selected from hydrogen; aliphatic, such as Ci1oaliphatic; aromatic, such as C5.

ioaromatic; or heteroaliphatic, such as Cioheteroaliphatic. In some embodiments, each of R2 and R3 independently is Ra, wherein R is hydrogen, methyl, ethyl,

propyl, butyl, pentyl, or hexyl. In particular embodiments, each of R 2 and R3 independently is hydrogen or methyl. In exemplary embodiments, R 2 is methyl and R3 is hydrogen.

In some embodiments, each R 4 independently and/or each Ri ndependently is Ra orRb, wherein Ra is independently for each occurrence alkyl, alkenyl, or alkynyl and wherein Rb is chloro, bromo, iodo, or fluoro. In particular embodiments, each R 4 and/or each Ri ndependently is lower alkyl or fluoro.

In some embodiments, m is 1; n is 0 or 1; and p is 0 or 1. In particular embodiments, m is 1, n is 0 and p is 0 or 1.

The compounds of Formula I can also have structures satisfying any one or more of Formulas II and IIA-IIC.

0 R1 NNR /0O

Formula II zzFomul IIAr Formula IIA N s R1~ 0 W Oorl R1 N H /0 FormulaT111

0 I R1 ~N NH - ~ /0 Formula IIC With reference to Formulas II and IIA-IIC, each of R and R 5 are as recited above for Formula I. In

particular embodiments, R' is Rb wherein Rb is -NRdRd and wherein two Rd groups together with the

nitrogen bound thereto provide a heterocyclic group substituted with two R° groups, wherein the R° groups are independently for each occurrence C 1.6 haloalkyl or C 1 .6 heteroalkyl or wherein the two R° groups join together to provide a C 3-ioheterocyclic group with the Rbgroup to which the two R° groups are bound. In

some embodiments, and the two R° groups a bicyclic group or a spirocyclic group. In particular embodiments, R 5 is present and is fluoro. In other particular embodiments, R5 is not present. With reference

to Formulas IIA-IIC, each W independently is nitrogen or oxygen. In some embodiments, the compounds of Formula I can also have structures satisfying any one or more of Formula III wherein R 1 is a heterocyclic group; Formulas IVA or IVB wherein R is a heterocyclic

group and further is a spirocyclic group; or Formulas VA, VB, or VC wherein R1 is a heterocyclic group and

further is a bicyclic group.

0

NNRB N Oor1 Re /0 Re Formula III o5 N R Oor1 Y / 0 Y Y

Formula IVA

0

N N NH BR50or1

Yy0

Formula IVB

0

HNH R5)

Formula VA

0 0

N 0Y R5

Formula VB

0'

/NN NH R51 YO/ 0

Formula VC With reference to Formula III, each R° is independently for each occurrence C 16 haloalkyl (e.g., alkyl-Cl, alkyl-Br, alkyl-F, or alkyl-I) or C 1 .6 heteroalkyl (e.g., alkyl-OH). In particular embodiments of Formula III,

one R° is -CH2 OH and the other Reis -CH 2C. With reference to Formulas IVA and IVB, each Y

independently is nitrogen, oxygen, or -C(Rf) 2-, wherein each Rf independently for each occurrence is hydrogen or C 1-Calkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In particular embodiments of Formula IVA, IVB, VA and VB, at least one Y is oxygen and the remaining Y variables are all -CH 2 -. In

particular embodiments of Formulas IVA, IVB, VA and VB, at least one Y is oxygen, for example at least one Y is oxygen and the remaining Y variables are all -CH 2-. In particular embodiments of Formula VC, Y is nitrogen or -CRf-, wherein Rf is hydrogen or aliphatic, particularly C1-Coalkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In particular embodiments of Formula VC, Xis nitrogen and Yis nitrogen. With reference to any one of Formulas111, IVA, IVB, and VA-VC,ring Bis

W W or W

Certain disclosed exemplary compounds within the scope of one or more of FormulasI1, IIA-IC, 5111IIVA, IVB, or VAVCinclude: 0

1-2;

0 0

04

1-3; 1-4; 0 0 _I N H

H 1-5; 1-6; 0 0

H'N F~

NN-/

-j 0 F

1-9; 1-8; o 0

--,,,[H ""' N N

0 ~ FH

I-il;1- 12;

1-13; 1-14; 0

N

0

1-16; 1-15; 0 0

NlN

1-17;1-8

0 0

0 F LiN 0I 0 N-H

1-19; 1-20; 0 0

00 /- 0-N 0 -0

1-23; 1-24; 0 0

1-25; 1-2; o 00

N [\HN

0 H--- 0 -- 1~ 0H

1-27.o

1-223-

Exemplary compounds within the scope of one or more of Formulas I-V, VIA, VIB, or VIIA-VIIC

include: I-1: (S)-N-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3

carboxamide;

1-2: (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl) 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 1-3: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5

tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide; 1-4: (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)

2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxaiide; 1-5: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-6: N-((S)-7-((iS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide; 1-7: N-((S)-7-((iS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

1-8: (S)-i-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-9: (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide; 1-10: (S)-5-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

I-11: (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl) 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 1-12: (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 1-13: N-((3S)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide; 1-14: (S)-N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

1-15: (S)-5-benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5

tetrahydrobenzo[b][1,4]oxazepin-3-yl)-iH-1,2,4-triazole-3-carboxaiide; 1-16: (S)-N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

1-17: (S)-5-benzyl-N-(7-((3-chloropropyl)amino)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxaiide;

I-18: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5

tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 1-19: (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)

2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-20: (S)-N-(7-(azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin

3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide; I-21: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-22: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-23: (S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-5-methyl-4 oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 1-24: (S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undecan-9-yl)-5-methyl-4

oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxaiide;

1-25: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; 1-26; (S)-5-benzyl-N-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxaiide; and 1-27: (S)-5-benzyl-N-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. Additional exemplary compound species contemplated by the present disclosure are illustrated below.

CC N F

N11'h 1 (H NH NNx

OHO CI OH

O 0- F 0 H <z- F

O N K ONN N 25 0 o 0 0 NH N -NH N+-u

/C 0 I 0

N 0 - F -N<. F NH NN _ a a NH NN N -NN N N / 0 /:p0 00

0 0 -<0 N"

NIaIN -NH NN NN- NHNN 0 /CP /CP0 0 0 0 0I ~~~NH N N H H0ON N0~ y0 H H

N'Q00N~ 0 NG(I Nj /0 /0<, H H HH

al~N1III NH F 0 F

0 / 0 0 / 0

00

NH N\-NHF\ Nr "

0 NN H N

/ 0 0 / 0

N NH-< NNz~ F

a NH NH NihaIINI-- F

/C 0 /C 0

NH N N H

/ 0 0/ 0

CO 0 0 NH)

NH N-0 N N HN /'NhIII& 0 0

N 0 0 Ia: NH N NH N

0 0

0 N <- NH 'NNH\ N

N N 0

/00

<'N"III NHNH 7 0H a '-NH WCH 7l' NN

0 0N

NH _NH \H N

I C o 0 N "

NH0 /0

03 0 0N

/ /

0 0

H 'a NH HN N NH NH

O'NN,/' ON N

N~aN -0 N a -NN

0__ (0

O N

ON N O NH O N N O /00

NN /0 /0< N N N N

0 0 NN N N

0 0

NH 'NNH NH NH ~

N N 0 0 O NO 0

CN NIQ O~N~

Fa FN 0/ N 0 0

N1( FN H N F jllI1 0 N N NH ' 0 N 0 0C

Ni~ N H\NNH 0N \>III

In some embodiments, one or more of the compounds can be included in apharmaceutical composition or medicament, and in some embodiments the compound or compounds can be inthe form of the parent compound or apharmaceutically acceptable salt, astereoisomer, an N-oxide, atautomer, a hydrate, asolvate, an isotope, or aprodrug thereof. The pharmaceutical composition typically includes at least one additional component other than adisclosed compound or compounds, such as apharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent (described in the following section), or any combination thereof. Pharmaceutically acceptable excipients can be included in pharmaceutical compositions for avariety of purposes, such as todilute apharmaceutical composition for delivery to asubject, to facilitate processing of the formulation, to provide advantageous material properties to the formulation, to facilitate dispersion from a delivery device, to stabilize the formulation (e.g., antioxidants or buffers), to provide a pleasant or palatable taste or consistency to the formulation, or the like. The pharmaceutically acceptable excipient(s) may include a pharmaceutically acceptable carrier(s). Exemplary excipients include, but are not limited to: mono-, di-, and polysaccharides, sugar alcohols and other polyols, such as, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitols, diphosphatidyl choline, and lecithin; bulking agents; buffers, such as phosphate and citrate buffers; anti-adherents, such as magnesium stearate; binders, such as saccharides (including disaccharides, such as sucrose and lactose,), polysaccharides (such as starches, cellulose,microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers, including hydroxypropylmethyl cellulose, shellac, corn protein zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, crosslinked sodium carboxymethyl cellulose, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavors and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla; lubricants (such as minerals, exemplified by talc or silica, fats, exemplified by vegetable stearin, magnesium stearate or stearic acid); preservatives (such as antioxidants exemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids, exemplified by cysteine and methionine, citric acid and sodium citrate, parabens, exemplified by methyl paraben and propyl paraben); colorants; compression aids; emulsifying agents; encapsulation agents; gums; granulation agents; and combinations thereof.

B. Combinations of Therapeutic Agents

The compounds described herein may be used alone, in combination with one another, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to, or in combination with, other established therapies. The compound or compounds or composition comprising the

compound (or compounds) may be administered once, or in plural administrations. In some embodiments, the compounds of the present invention may be used in combination with other therapeutic agents useful for

the disorder or condition being treated. These other therapeutic agents may be administered simultaneously, sequentially in any order, by the same route of administration, or by a different route as the presently disclosed compounds. For sequential administration, the compound(s) and the therapeutic agent(s) may be

administered such that an effective time period of at least one compound and the therapeutic agent overlaps

with an effective time period of at least one other compound and/or therapeutic agent. In an exemplary embodiment of a combination comprising four components, the effective time period of the first component administered may overlap with the effective time periods of the second, third and fourth components, but the

effective time periods of the second, third and fourth components independently may or may not overlap with one another. In another exemplary embodiment of a combination comprising four components, the effective time period of the first component administered overlaps with the effective time period of the second component, but not that of the third or fourth; the effective time period of the second component overlaps with those of the first and third components; and the effective time period of the fourth component overlaps with that of the third component only. In some embodiments, the effective time periods of all compounds and/or therapeutic agents overlap with each other. In some embodiments, the compounds are administered with another therapeutic agent, such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral, anticancer, antifungal, or a combination thereof. The anti-inflammatory agent may be a steroid or a nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, antilymphocyte globulin, antithymocyte globulin, an anti-T-cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab. In some embodiments, the present compounds may be used with anti-cancer or cytotoxic agents.

Various classes of anti-cancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum

coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, for example DNMT inhibitors, such as azacitidine and decitabine. Exemplary alkylating agents include, without limitation, mechlorothamine, cyclophosphamide, ifosfamide,

melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan), and

carmustine. Exemplary antimetabolites include, by way of example and not limitation, folic acid analog methotrexate; pyrmidine analog fluorouracil, cytosine arbinoside; purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, by way of example and notlimitation,

vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme effective as an anti

neoplastic agent includes L-asparaginase. Exemplary coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Exemplary hormones and hormone related compounds include, by way of example and not limitation, adrenocorticosteroids prednisone and dexamethasone; aromatase

inhibitors amino glutethimide, formestane, and anastrozole; progestin compounds hydroxyprogesterone

caproate, medroxyprogesterone; and anti-estrogen compound tamoxifen. These and other useful anti-cancer compounds are described in Merck Index, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of

Therapeutics, 12th Edition, Brunton L.L. ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated by reference herein.

Among the CTLA 4 antibodies that can be used in combination with the presently disclosed

inhbitors is ipilimumab, marketed as YERVOY© by Bristol-Myers Squibb. Other chemotherapeutic agents for combination include immunooncology agents, such as checkpoint pathway inhibitors, for example, PD-i inhibitors, such as nivolumab and lambrolizumab, and

PD-Li inhibitors, such as pembrolizumab, MEDI-4736 and MPDL3280A/RG7446. Additional checkpoint inhibitors for combination with the compounds disclosed herein include, Anti-LAG-3 agents, such as BMS 986016 (MDX-1408). Further chemotherapeutic agents for combination with the presently disclosed inhibitors include

Anti-SLAMF7 agents, such as the humanized monoclonal antibody elotuzumab (BMS-901608), anti-KIR agents, such as the anti-KIR monoclonal antibody lirilumab (BMS-986015), and anti-CD137 agents, such as

the fully human monoclonal antibody urelumab (BMS-663513). The presently disclosed compounds also may be used advantageously with CAR-T therapies. Example of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

Additional anti-proliferative compounds useful in combination with the compounds of the present

invention include, by way of example and not limitation, antibodies directed against growth factor receptors (e.g., anti-Her2); and cytokines such as interferon-a and interferon-y, interleukin-2, and GM-CSF. Additional chemotherapeutic agents useful in combination with the present compounds include

proteasome inhibitors, such as bortezomib, carfilzomib, marizomib and the like. Examples of kinase inhibitors that are useful in combination with the presently disclosed

compounds, particularly in treating malignancies include: Btk inhibitors, such as ibrutinib; CDK inhibitors, such as palbociclib; EGFR inhibitors, such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib and vandetinib; Mek inhibitors, such as trametinib; Raf inhibitors, such as dabrafenib, sorafenib and

vemurafenib; VEGFR inhibitors, such as axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors,

such as bosutinib, dasatinib, imatinib and nilotinib; FLT-3 inhibitors, such as gilteritinib and quizartinib, P13-kinase inhibitors, such as idelalisib, Syk inhibitors, such as fostamatinib; and JAK inhibitors, such as ruxolitinib and fedratinib.

In other embodiments, the second therapeutic agent may be selected from any of the following: analgesics-morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone,

buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

antibiotics-aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and

meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cephalexin, cefaclor, cefamandole,

cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancin), lincosamides (e.g., clindamycin and incomysin), lipopeptides

(e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicilllins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate), polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxaxzole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others, such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuprisin/dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole; antibodies-anti-TNF-a antibodies, e.g., infliximab (Remicade TM ),adalimumab,golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-i antibodies, e.g., anakinra; anti PD-i and/or anti-PD-Li antibodies, e.g. nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; anticoagulants-warfarin (Coumadin T M ), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin; anti-inflammatory agents-steroids, e.g., budesonide, nonsteroidal anti-inflammatory agents, e.g., aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; immunosuppressants-mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus, inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolate, mycophenolate mofetil and azathioprine, and agents designed to suppress cellular immunity while leaving the recipient's humoral immunologic response intact, including various antibodies (for example, antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) and irradiation. Azathioprine is currently available from Salix

Pharmaceuticals, Inc. under the brand name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the brand name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; Methyl prednisolone is currently available from Pfizer; sirolimus

(rapamycin) is currently available from Wyeth-Ayerst under the brand name Rapamune; tacrolimus is currently available from Fujisawa under the brand name Prograf; cyclosporine is current available from Novartis under the brand name Sandimmune and Abbott under the brand name Gengraf; IMPDH inhibitors

such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand

name Cellcept and Novartis under the brand name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the brand name Imuran; and antibodies are currently available from Ortho Biotech under the brand name Orthoclone, Novartis under the brand name Simulect (basiliximab) and Roche under the

brand name Zenapax (daclizumab); and Guanylate cyclase-C receptor agonists or intestinal secretagogues, for example linaclotide, sold

under the name Linzess. These various agents can be used in accordance with their standard or common dosages, as specified in the prescribing information accompanying commercially available forms of the drugs (see also, the

prescribing information in the 2006 Edition of The Physician's Desk Reference), the disclosures of which are

incorporated herein by reference.

III. Methods of Making Compounds Disclosed compounds can be prepared by any acceptable synthetic method as will be understood by a person of ordinary skill in the art with the benefit of the present disclosure. One suitable method is

exemplified below, as illustrated for specific compounds in the examples. An exemplary method of making the compounds can include the following first reaction step according to Scheme 1.

I NHPG

m R2 Metal-Mediated, Cross-Coupling NHPG 100 (R R

R1-H 104 102

Scheme 1 With reference to Scheme 1, starting compound 100 is reacted with an R-containing reagent 102 using

suitable metal-mediated, cross-coupling conditions to provide R-functionalized product 104. X is a suitable group for metal-mediated cross-coupling, such as a halogen or a triflate group and PG is an amine protecting group, which can be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a t

butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a

benzyloxycarbonyl ("Cbz") group, and the like. In some embodiments, the metal-mediated, cross-coupling conditions comprise using a transition metal catalyst, such as a Pd(0) catalyst (e.g., Pd 2(dba) 3 , Pd(dba) 2 ,

Pd(PPh 3)4 , and the like) in combination with a ligand component, such as a ligand capable of generating

Pd(II) from the Pd(0) catalyst (e.g., a BINAP ligand, a BINOL ligand, and the like), a base (e.g., t-BuONa), and a solvent. In some embodiments, the cross-coupling step involves heating the reaction mixture at a suitable temperature (e.g., 60 °C or higher, such as 70 °C to 140 °C, or 80 °C to 120 °C, or 85 °C to 100 C). Representative examples of the method shown in Scheme 1 are provided below in Schemes 2A-2G.

NH HCI HO

NHTr CIN 'NHTr B Pd 2(dba) 3, BINAPt-BuONa HO toluene, 85°C,o/n

200 CI 202

Scheme 2A

O0 NH HCIO 1NHTr N7NINHTr Br N Pd 2 (dba) 3, BINAP,t-BuONa N / 0 toluene, 85 °C,o/n 0 /0

200 204

Scheme 2B

0 NHTr HNI HNN O 0 NHTr Br N Pd2 (dba) 3, BINAPt-BuONa N toluene, 85 °C,o/n I 200 206

Scheme 2B H

NH HCI

1NHTr NNHTr Br Pd2 (dba) 3, BINAPt-BuONa rN i 0 toluene, 85 C,o/n

200 208

Scheme 2D

NH HCI

1NHTr N NHTr Br N Pd 2 (dba) 3, BINAPt-BuONa NN °C,o/n 0 toluene, 85

200 210

Scheme 2E

OHOO

INHTr NINHTr Br N Pd2(dba)3, BINAPt-BuONa N 0 toluene, 85 °C,o/n

200 212

Scheme 2F

HCI

1NHTr NH I 'NHTr Br N Pd 2 (dba) 3, BINAP,t-BuONa NN 0 1' 0 toluene, 85 C,o/n 0

200 214

Scheme 2G Embodiments of the method for making the compounds can further comprise additional steps used

to transform R1 -functionalized product 104 into desired compounds within the scope of the present disclosure. In some embodiments, these additional steps can include a first deprotection step to provide amine compound 300. Amine compound 300 is then converted into amide compound 304 by reacting the

amine compound with a suitable acid coupling partner 302, as illustrated in Scheme 3.

NHPG Deprotection AR NH 2 HO L R N O Aj R NN(p)' (RR'~o (1"N Amide Formation 42 0 102 300 304

Scheme 3 With reference to Scheme 3, deprotection can involve using any suitable reagent capable of removing an amine protecting group ("PG" as shown in Schemes 1 and 3). In some embodiments, an acid is used in the

deprotection step, such as TFA. In yet additional embodiments, a base can be used in the deprotection step, such as piperidine. Other acids and bases suitable for deprotection are readily recognized by those of

ordinary skill in the art with the benefit of the present disclosure. The amide formation step can be carried out using reagents capable of facilitating amide formation between the free amine of amine compound 300 and the acid functional group of acid coupling partner 302. Suitable coupling partners can be synthesized

using methods recognizable to those of ordinary skill in the art with the benefit of the present disclosure, or

can be purchased from commercial sources. In some embodiments, propylphosphonic anhydride can be used in combination with a base, such as diisopropylethylamine for amide formation; however, other reagents can be used, such as 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium

hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-N,N,N',N'-hexafluorophosphate, 2-(6-chloro-1H benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium hexafluorophosphate, 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N' ethylcarbodiimide- HCl, benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate, bromo-tripyrrolidino-phosphonium hexafluorophosphate, and the like, in combination with di-isopropylethyl amine, isopropyl amine, and the like. A suitable solvent also is used, such as dichloromethane ("DCM").

Representative examples of the method steps shown in Scheme 3 are provided below in Schemes 4A-4N.

'-NHTr N HO / O

cI 202

TFA DCM, rt, 30 min

o F 1H -Iy- N-N 0 0 N-~N

N -'NH 400 N CO 2H HONNF

T 3P, DIPEA, DCM, rt 0 CI 203 CI I-1

Scheme 4A

N NHTr / 0 O> 204

TFA DCM, rt, 30 min

F

0 NH N-N 0 0>"NN N NH2 400 (1N C2

O 205 T 3 P, DIPEA, DCM, rt 0

1-2

Scheme 4B

'NHTr

/ 0 204

TFA DCM, rt, 30 min

402 NNH2CO 2 H N N O 0 T 3P, DIPEA, DCM, rt O 0,_, 205 0C 1-3

Scheme 4C

N'iNI~-NHTr /0 00 206

FF

FCI,-- N-N0 'NH2 400 NH"/I __j N N')IC0 2HN / 0 ( N 0 T 3P, DIPEA, DCM, rt 000 207 0 1-4

Scheme 4D

NJKI'a N 'NHTr /0 0a j 204

TFA DCM, rt, 30min

INH2 406 N 1: NN- / 0 T3PDIPEA, DCM, rt 00

0 205 1-5

Scheme 4E

H . ):: oN "NHTr

0ID / 0 208

TFA ~DCM, rt, 30min 0 0

H 42 'N C02H H NHN -o

/0K J 3P, DIPEA,0DCM, rt T 5209 1-6

Scheme 4F

,NHTr

208 {TA DICK rt, 30min

Ha ~o 400 NC0 2 H 0 IN

T 3 P, DIPEADOM, rt O ©I 0 209 1-7

Scheme 4G

"NHTr /0 0j 210/

TFA DCM, rt, 30 min F- /1 1 0

'N 2 400 -N~C0 2 H N' 0~,H

/ 0 T3P, DIPEA, DCM,~r 0

2111

Scheme 4H

N'a N -'NHTr /0 0j 210

0CM, rt,30 0

- 40H2 12 0, C0 2H Na N 0 TPDE0Mr N 0 00 0 211 1-9

Scheme 41

ji 0 'NHTr

J/ 0 0 210

DCMrt,30 min N~N~

HN N)' 02 ao'NH 0 -NH 2 406 0 T3P, DIPEA,0DCM, r 211 5 1-10

Scheme4Q

NI~INHTr /0 0C 204 S TFA DCM, rt, 30min

0 0. 406 HN -- C2 "NH2 OHN~~- N N-NH F / 0T3P, DIPEA,0DCM, r 0 : 205

Scheme 4K

N HNT / 0 0 210

TFA DCM, rt, 30 min

0 - -N ~0 - ' -r-H"

408 HN, C NI

N 0 T 3 P, DIPEA, DCM, rt O

211 1-12

Scheme 4L

NHTr

212 TFA DCM rt, 30 min

0

JiIN'N 2 0 NH 2 402 IN CO7H T 3P, DIPEA, DCM, rt0 NINH -O

213 1-13

Scheme 4M 0

N NHTr N /0 214 TFA DCM, rt, 30 min

00

.>NH2 IN 4COH N112 T 3P, DIPEA, DCM, rt N N

215 1-14

Scheme 4N With reference to Schemes 4A-4N above, acid coupling partner 402 can be made using the following procedure: A solution of the ethyl 5-benzylisoxazole-3-carboxylate is dispensed into a solution of NaOH in

MeOH and water. After standing for a suitable time at 20 °C, the solvent is removed in vacuo. The residue is acidified with dilute HCl and then extracted with EtOAc. The organic phase is washed with water and

saturated brine, and dried over sodium sulphate, followed by evaporation in vacuo. The other acid coupling partners described in Schemes 4A-4N can be made using a similar method starting with a suitable starting

material (e.g., ethyl 5-benzyl-1H-1,2,4-triazole-3-carboxylate, ethyl 1-benzyl-1H-1,2,4-triazole-3 carboxylate, and fluorinated versions thereof).

IV. Methods of Using Compounds A. Diseases/Disorders The disclosed compounds, as well as combinations and/or pharmaceutical compositions thereof, may be used to inhibit a RIPi kinase by contacting the kinase either in vivo or ex vivo, with a compound or

compounds of the present disclosure, or a composition comprising a compound or compounds of the present

disclosure. Disclosed compound or compounds, or compositions comprising a disclosed compound or compounds also can be used to ameliorate, treat or prevent a variety of diseases and/or disorders. In particular embodiments, the disclosed compound, combinations of disclosed compounds, or pharmaceutical

compositions thereof, may be useful for treating conditions in which inhibition of RIPi or a pathway involving RIPi is therapeutically useful. In some embodiments, the compounds directly inhibit RIPi kinase

activity. In certain embodiments, disclosed compounds are useful for treating auto-immune diseases, inflammatory disorders, cardiovascular diseases, nerve disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancers, ischemic conditions, erythrocyte deficiencies, lung

and brain injuries (e.g., induced by ischemia-reperfusion or cisplatin and/or cerebrovascular accident), and

bacterial and viral infections. In some embodiments, the disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof, may be used to treat or prevent allergic diseases, amyotrophic lateral

sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative

colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmyopathy, or asthma. The disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions

thereof, may also be useful for treating immune regulatory disorders related to bone marrow or organ

transplant rejection or graft-versus-host disease. Examples of inflammatory and immune regulatory disorders that can be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, transplantation of organs or tissue, graft-versus-host diseases brought about

by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome,

myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, postinfectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis,

eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis

bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, ischemia-reperfusion injuries, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis or myocardial infarction, scleroderma (including systemic scleroderma), anti-phospholipid syndrome,

Wegener's granuloma, Sj6gren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium,

alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of

organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic

renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous

dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by

environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis,

shock, or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune

hepatobiliary diseases, acetaminophen toxicity, hepatotoxicity, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic" liver failure, chronic kidney diseases, kidney damage/injury (caused by, for example, nephritis, renal transplant, surgery, administration of nephrotoxic drugs, acute

kidney injury), augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection,

AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection. In certain embodiments the present compounds are useful for treating nerve pain, including neuropathic pain and inflammation induced pain.

In certain embodiments, the compounds are useful for treating interleukin-1 converting enzyme associated associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sach disease, and

Wolman disease). In certain embodiments, the disclosed compound, combinations of disclosed compounds, or

pharmaceutical compositions thereof, are useful for treating and/or preventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, in particular pustular psoriasis, type I diabetes, type II

diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d

and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult's onset Still's disease, gout, gout flares, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor

antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease. Proliferative diseases that may be treated by the disclosed compound, combinations of disclosed

compounds, or pharmaceutical compositions thereof, include benign or malignant tumors, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or

thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially

colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas,

Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL- Idriven disorders, a MyD88 driven disorder (such as ABC

diffuse large B-cell lymphoma (DLBCL), Waldenstr6m's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-celllymphoma or chronic lymphocytic leukemia),smoldering or indolent multiple myeloma, or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL,

ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion

lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstram's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple

myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the presently disclosed compounds are useful in treating drug resistant malignancies, such as those resistant to JAK inhibitors ibrutinib resistant malignancies, including ibrutinib resistant hematological malignancies, such as ibrutinib resistant CLL and ibrutinib resistant Waldenstr6m's macroglobulinemia. Examples of allergic disorders that may be treated using the disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof, include, but are not limited to, asthma (e.g.

atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma,

non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, essential asthma of unknown or unapparent cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air induced

asthma, occupational asthma, infective asthma caused by or associated with bacterial, fungal, protozoal, or viral infection, incipient asthma, wheezy infant syndrome, bronchiolitis, cough variant asthma or drug

induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, post-nasal drip, purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion and

tenderness of targetjoints throughout the body. RA is characterized by chronically inflamed synovium that is densely crowded with lymphocytes. The synovial membrane, which is typically one cell layer thick, becomes intensely cellular and assumes a form similar to lymphoid tissue, including dendritic cells, T-, B

and NK cells, macrophages and clusters of plasma cells. This process, as well as a plethora of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, eventually

result in destruction of the integrity of the joint, resulting in deformity, permanent loss of function and/or bone erosion at or near the joint. The disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof, may be used to treat, ameliorate or prevent any one, several or all of

these symptoms of RA. Thus, in the context of RA, the compounds are considered to provide therapeutic

benefit when a reduction or amelioration of any of the symptoms commonly associated with RA is achieved, regardless of whether the treatment results in a concomitant treatment of the underlying RA and/or a reduction in the amount of circulating rheumatoid factor ("RF").

The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission in RA. Once such parameter, the ACR20 (ACR criteria for 20% clinical

improvement), requires a 20% improvement in the tender and swollen joint count, as well as a 20% improvement in 3 of the following 5 parameters: patient's global assessment, physician's global assessment, patient's assessment of pain, degree of disability, and level of acute phase reactant. These criteria have been

expanded for 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include

Paulu's criteria and radiographic progression (e.g. Sharp score). In some embodiments, therapeutic benefit in patients suffering from RA is achieved when the patient exhibits an ACR20. In specific embodiments, ACR improvements of ACRC50 or even ACR70 may

be achieved.

B. Formulations and Administration

Pharmaceutical compositions comprising one or more active compounds of the invention may be manufactured by any suitable method, such asmixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilization processes. The pharmaceutical compositions may

be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers, or

auxiliaries), one or more adjuvants, or combinations thereof to provide preparations which can be used pharmaceutically. The active compound(s) may be formulated in the pharmaceutical compositions per se, or in the

form of a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof. Typically, such salts are more soluble in aqueous solutions than the

corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed. Pharmaceutical compositions of the invention may take a form suitable for virtually any mode of

administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, such as i.v. or

i.p., transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation. For topical administration, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug may be formulated as solutions, gels, ointments,

creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous,

intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. Useful injectable preparations include sterile suspensions, solutions or emulsions of the active

compound(s) in aqueous or oily vehicles. The pharmaceutical compositions may also contain formulating

agents, such as suspending, stabilizing and/or dispersing agent. The formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile, pyrogen-free water, buffer, dextrose solution, etc.,

before use. To this end, the active compound(s) maybe dried by any art-known technique, such as lyophilization, and reconstituted prior to use. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in

the formulation. Such penetrants are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as: binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl

methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and/or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art with, for example, sugars, films or enteric coatings. Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable excipients such as: suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore' T M or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound, as is well known. For buccal administration, the pharmaceutical compositions may take the form of tablets or lozenges

formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases, such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug can

be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g.,) dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may

be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an

inhaler or insufflator (for example capsules and cartridges comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. A specific example of an aqueous suspension formulation suitable for nasal administration using

commercially-available nasal spray devices includes the following ingredients: active compound (0.5 20 mg/ml); benzalkonium chloride (0.10.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5 5 mg/ml); carboxymethycellulose sodium or microcrystalline cellulose (1 15 mg/ml); phenylethanol (14 mg/ml); and dextrose (20 50 mg/ml). The pH of the final suspension can be adjusted to range from about pH 5 to pH 7, with a pH of about pH 5.5 being typical. Another specific example of an aqueous suspension suitable for administration of the compounds

via inhalation contains 20 mg/mL of the disclosed compound(s), 1% (v/v) polysorbate 80 (TWEEN® 80), 50 mM citrate and/or 0.9% sodium chloride.

For ocular administration, the active compound(s) may be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Pat. Nos.

6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporated herein by reference. For prolonged delivery, the active compound(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient maybe formulated with

suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange

resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the active compound(s) for percutaneous absorption may be used. To this end, permeation enhancers may be used to facilitate

transdermal penetration of the active compound(s). Suitable transdermal patches are described in for example, U.S. Pat. Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference. Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s). Certain

organic solvents, such as dimethylsulfoxide (DMSO), may also be employed, although usually at the cost of

greater toxicity. The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The pack may, for example,

comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

C. Dosages The disclosed compound, pharmaceutical compositions, or combinations of disclosed compounds

will generally be used in an amount effective to achieve the intended result, for example, in an amount

effective to inhibit a RIPi kinase and/or to treat, prevent or ameliorate a particular condition. The disclosed compound(s), or pharmaceutical compositions thereof, can be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve a prophylactic benefit. Therapeutic benefit means

eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an

improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides therapeutic benefit not only when the underlying allergic response is eradicated or ameliorated, but

also when the patient reports a decrease in the severity or duration of the symptoms associated with the

allergy following exposure to the allergen. As another example, therapeutic benefit in the context of asthma includes an improvement in respiration following the onset of an asthmatic attack or a reduction in the frequency or severity of asthmatic episodes. Therapeutic benefit also includes halting or slowing the

progression of the disease, regardless of whether improvement is realized.

As known by those of ordinary skill in the art, the preferred dosage of disclosed compounds may

depend on various factors, including the age, weight, general health, and severity of the condition of the patient or subject being treated. Dosage also may need to be tailored to the sex of the individual and/or the lung capacity of the individual, when administered by inhalation. Dosage may also be tailored to individuals

suffering from more than one condition or those individuals who have additional conditions that affect lung

capacity and the ability to breathe normally, for example, emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory infections. Dosage, and frequency of administration of the disclosed compound(s) or pharmaceutical compositions thereof, will also

depend on whether the disclosed compound(s) are formulated for treatment of acute episodes of a condition or for the prophylactic treatment of a disorder. A person of ordinary skill in the art will be able to determine

the optimal dose for a particular individual. For prophylactic administration, the disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof, can be administered to a patient or subject at risk of developing one of

the previously described conditions. For example, if it is unknown whether a patient or subject is allergic to

a particular drug, the disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof, can be administered prior to administration of the drug to avoid or ameliorate an allergic response to the drug. Alternatively, prophylactic administration can be used to avoid or ameliorate

the onset of symptoms in a patient diagnosed with the underlying disorder. For example, a disclosed compound(s), or pharmaceutical composition thereof, can be administered to an allergy sufferer prior to

expected exposure to the allergen. A disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof, can also be administered prophylactically to healthy individuals who are repeatedly exposed to agents known to one of the above-described maladies to prevent the onset of the

disorder. For example, a disclosed compound, combinations of disclosed compounds, or pharmaceutical

compositions thereof, can be administered to a healthy individual who is repeatedly exposed to an allergen known to induce allergies, such as latex, in an effort to prevent the individual from developing an allergy. Alternatively, a disclosed compound, combinations of disclosed compounds, or pharmaceutical

compositions thereof, can be administered to a patient suffering from asthma prior to partaking in activities which trigger asthma attacks to lessen the severity of, or avoid altogether, an asthmatic episode.

Effective dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in subjects can be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC5 0 or EC5 o of the particular compound as measured in an in vitro assay. Dosages can

be calculated to achieve such circulating blood or serum concentrations taking into account the

bioavailability of the particular compound. Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and the references cited therein, provide additional guidance concerning effective dosages.

In some embodiments, the disclosed compounds have an EC 5 ofrom greater than 0 to 20 pM, such as

from greater than 0 to 10 pM, from greater than 0 to 5 pM, from greater than 0 to1I pM, from greater than 0 to 0.5 pM, from greater than 0 to 0.1 pM, or from greater than 0 to 0.05 pM. Initial dosages can also be estimated from in vivo data, such as animal models. Animal models

useful for testing the efficacy of compounds to treat or prevent the various diseases described above are

well-known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50(2lSuppl):6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol. 107(6):1025-1033. Suitable animal models of allergic rhinitis are described in Szelenyi et al.,

(2000), Arzneimittelforschung 50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7. Persons of ordinary skill in the art can adapt

such information to determine dosages suitable for human administration. In some embodiments, assays suitable for determining RIPI activity can be used. Such assay methods can be used to evaluate the efficacy of compound embodiments disclosed herein and/or that can be

used to determine amounts/dosages of the compound embodiments that can provide a desired efficacy. In

some embodiments, the assay can be an ADP-GloTM assay that assesses the ability of a compound embodiment to inhibit RIPI. In other embodiments, whole cell assays using mouse and/or human cells, such as U937 and/or L929 cell necroptosis assays, can be performed to determine safe and effective doses of

compounds that can be used in human in vivo studies. Using these whole cell assays, the compound's activity against human and/or murine RIP Ican be assessed in an in vitro context, which then allows a

person of ordinary skill in the art to determine safe and effective dosages for in vivo use. Yet another assay that can be used to evaluate the activity of compound embodiments described herein to treat a disease or condition involving RIPI is an acute hypothermia mouse model, which assesses the compound's ability to

inhibit TNF-alpha induced hypothermia. Each of these assays, and various results from using these assays,

are described in detail in the Examples section of the present disclosure. Dosage amounts of disclosed compounds will typically be in the range of from greater than 0

mg/kg/day, such as 0.0001 mg/kg/day or 0.001 mg/kg/day or 0.01 mg/kg/day, up to at least about 100

mg/kg/day. More typically, the dosage (or effective amount) may range from about 0.0025 mg/kg to about 1 mg/kg administered at least once per day, such as from 0.01 mg/kg to about 0.5 mg/kg or from about 0.05

mg/kg to about 0.15 mg/kg. The total daily dosage typically ranges from about 0.1 mg/kg to about 5 mg/kg or to about 20 mg/kg per day, such as from 0.5 mg/kg to about 10 mg/kg per day or from about 0.7 mg/kg per day to about 2.5 mg/kg/day. Dosage amounts can be higher or lower depending upon, among other

factors, the activity of the disclosed compound, its bioavailability, the mode of administration, and various

factors discussed above. Dosage amount and dosage interval can be adjusted for individuals to provide plasma levels of the disclosed compound that are sufficient to maintain therapeutic or prophylactic effect. For example, the

compounds can be administered once per day, multiple times per day, once per week, multiple times per week (e.g., every other day), one per month, multiple times per month, or once per year, depending upon, amongst other things, the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. Persons of ordinary skill in the art will be able to optimize effective local dosages without undue experimentation. Pharmaceutical compositions comprising one or more of the disclosed compounds typically comprise from greater than 0 up to 99% of the disclosed compound, or compounds, and/or other therapeutic agent by total weight percent. More typically, pharmaceutical compositions comprising one or more of the disclosed compounds comprise from about 1 to about 20 total weight percent of the disclosed compound and other therapeutic agent, and from about 80 to about 99 weight percent of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition can further comprise an adjuvant. Preferably, the disclosed compound, combinations of disclosed compounds, or pharmaceutical compositions thereof, will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the disclosed compound can be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Disclosed compounds that exhibit high therapeutic indices are preferred.

V. Examples Example 1

O O NH HCI 0 'NHTr - NHTr ''\' TFA Br N Pd 2(dba) 3, BINAPt-BuONa N N DCM, rt, 30 min 0 / O toluene, 85 C,o/n e/ 2 200 Step 1 204(96%)

0 N 0-N NH

O N i''NH2 N CO 2 H

"/ T 3P, DIPEA, DCM, rt O N

205(91%) Step 3 1-5(61%)

Step 1 - A mixture of (S)-7-bromo-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

200 (which is made using a method as illustrated below; 0.25 g, 0.49 mmol), 7-oxa-2-azaspiro[3.5]nonane hydrochloride (0.10 g, 0.60 mmol), Pd 2(dba)3 (0.025 g, 0.027 mmol), rac-BINAP (0.05 g, 0.08 mmol) and NaO'Bu (0.12 g, 1.3 mmol) in toluene (5 mL) was stirred at 85 °C for 16 hours. The reaction mixture was

then concentrated under reduced pressure to give a residue, which was purified by chromatography eluting

with ethyl acetate/hexanes (3/7) to provide (S)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-3 (tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 204 as a brown solid (0.26 g, 96%).

HBoc iPr2 NEt, HATU F Mei, Cs2CH3 F 0O O DMIto1 r~~' INHBoc Br NH0I Ho O DMF, 0 °C to rt, 16h H DMF,rt,16 B

HCI, Dioxane Fr-H Br' NH2 I r,3

B "NHTr Cs2CO 3,DMF B' NBr C Br - -~----------NH~ N CHC 3O 0 C,4hI ~Br - Br N NH N TrI , Et3N,4

/ 0 5OIC, 1.5d OH OH

200

Exemplary method for making compound 200 Step 2 - To a mixture of (S)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(tritylamino)-2,3 dihydrobenzo[b][1,4]oxazepin-4(5H)-one 204 (0.26 g, 0.46 mmol) in dichlomethane (6 mL) was added

trifluoroactic acid (15.7 mmol, 1.2 mL). The resulting solution was stirred at room temperature for 0.5 hours. The solution was then concentrated under reduced pressure. The residue was dissolved in methanol

and subsequently basified by 28% ammonium hydroxide solution. The resulting mixture was re concentrated under reduced pressure to give a residue, which was purified by chromatography eluting with

ethyl acetate to dichloromethane/MeOH (10/2) to provide (S)-3-amino-5-methyl-7-(7-oxa-2 azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 205 as a pale white solid (0.16 g, 1 91%). H NMR (CD 30D, 400 MHz) 6.96 (d, J= 8.8 Hz, 1H), 6.38 (d, J= 2.8 Hz, 1H), 6.32 (dd, J= 8.8, 2.8 Hz, 1H), 4.30 (m, 1H), 3.98 (m, 1H), 3.72 (m, 1H), 3.64 (m, 8H), 3.33 (s, 3H), 1.81 (m, 4H) ppm;MS m/e: 318.2 (M+H)*.

Step 3 - To a stirred mixture of (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3

dihydrobenzo[b][1,4]oxazepin-4(5H)-one 3 (0.025 g, 0.08 mmol) 205 and 5-benzyl-1H-1,2,4-triazole-3 carboxylic acid (0.018 mg, 0.09 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine

(0.05 ml, 0.3 mmol) and T 3P (propylphosphonic anhydride solution (50% wt. % in ethyl acetate). The reaction mixture was stirred at room temperature for 3 hours and quenched with water. The organic layer

was separated and concentrated under reduced pressure to give a residue, which was purified by chromatography eluting with ethyl acetate/hexanes (3/7 to 9/1) to provide (S)-5-benzyl-N-(5-methyl-4-oxo 7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3

carboxamide 1-5 as a white solid (0.02 g, 61%). 1H NMR (CD30D, 400 MHz) 7.26 (m, 5H), 7.01 (d, J= 8.8 Hz, 1H), 6.43 (d, J= 2.8 Hz, 1H), 6.36 (dd, J= 9.0, 2.4 Hz,1H), 4.96 (m,1H), 4.47 (m, 1H), 4.25 (m,1H),

4.13 (s, 2H), 3.64 (m, 8H), 3.35 (s, 3H), 1.82 (m, 4H) ppm;MS me: 503.3 (M+H)*.

Example 2 The synthetic procedure described above was adapted as described herein to make compound I-I

below.

"NH N/ HO 0 F C

I-1 (S)-N-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5 1 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide H NMR

(CD 30D, 400 MHz) 8.56 (s, 1H), 7.82 (m, 1H), 7.65 (m, 1H), 7.38 (m, 2H), 7.07 (m, 3H), 5.43 (s, 2H), 5.00 (m, 1H), 4.60 (m, 1H), 4.49 (m, 1H), 4.40 (m, 2H), 3.43 (s, 3H), 2.38 (m, 2H), 2.02 (m, 2H), 1.35 (m, 6H)

ppm; MS mle: 557.3 (M+H)*. Example 3

The synthetic procedure described above was adapted as described herein to make compound 1-2 below.

00 -""NH -N NW

/ 0 0 F

1-2 (S)-i-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5 1 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide H NMR (CDCl 3 , 400 MHz) 8.01 (m, 2H), 7.26 (m, 2H), 7.05 (m, 3H), 6.26 (dd, J= 9.0, 2.8 Hz, 1H), 6.18 (d, J= 2.8 Hz, 1H), 5.33 (s, 2H), 5.08 (m, 1H), 4.65 (m, 1H), 4.13 (m, 1H), 3.65 (m, 8H), 3.38 (s, 3H), 1.85 (m, 4H) ppm; MSm/e: 521.3 (M+H)*. Example 4 The synthetic procedure described above was adapted as described herein to make compound 1-3 below. 0

- ""NH

0C

1-3 (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide H NMR (CDC 3, 400 MHz) 7.69 (m, IH),

7.26 (m, 5H), 7.01 (d, J= 8.8 Hz, 1H), 6.26 (m, 2H), 6.18 (d, J= 2.8 Hz, 1H), 5.00 (m, 1H), 4.61 (m, 1H), 4.13 (m, 1H), 4.08 (s, 2H), 3.64 (m, 8H), 3.38 (s, 3H), 1.84 (m, 4H) ppm;MS me: 503.3 (M+H)*. Example 5 The synthetic procedure described above was adapted as described herein to make compound 1-4

below.

0

NH N NN:::::: N/0

F

1-4 (S)-I-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3,4,5 1 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide H NMR (CD 3 0D, 400 MHz) 8.56

(s, 1H), 7.40 (m, 2H), 7.09 (m, 3H), 6.96 (m, 1H), 6.90 (m, 1H), 5.45 (s, 2H), 4.97 (m, 1H), 4.51 (m, 1H), 4.49 (s, 4H), 4.31 (m, 1H), 3.38 (s, 3H), 3.12 (m, 4H), 2.01 (m, 4H) ppm;MSm/e: 521.3 (M+H)*. Example 6

The synthetic procedure described above was adapted as described herein to make compound 1-6 below.

0 H I **""NHI ON O N- 0

H

1-6 N-((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5 1 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide H NMR (CD 30D, 400 MHz) 7.28

(m, 5H), 7.02 (d, J= 8.8 Hz, 1H), 6.58 (m, 1H), 6.53 (dd, J= 8.4, 2.8 Hz, 1H), 6.37 (s, 1H), 4.96 (m, 1H), 4.63 (m, 1H), 4.51 (m, 1H), 4.45 (m, 1H), 4.30 (m, 1H), 4.14 (s, 2H), 3.83 (m, 2H), 3.55 (m, 1H), 3.36 (s,

3H), 3.07 (m, 1H), 2.02 (m, 1H), 1.93 (m,1H) ppm; MSm/e: 475.1 (M+H)*. Example 7 The synthetic procedure described above was adapted as described herein to make compound 1-7

below.

0 HNH

N/

00 F H

1-7 N-((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5 1 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide H NMR (CD 30D, 400 MHz) 8.54 (s, 1H), 7.38 (m, 2H), 7.06 (m, 3H), 6.59 (d, J= 2.8 Hz, 1H), 6.54 (dd, J= 8.4, 2.8 Hz, 1H), 5.43 (s, 2H), 4.97 (m, 1H), 4.63 (m, 1H), 4.49 (m, 2H), 4.26 (m, 1H), 3.83 (m, 2H), 3.55 (m, 1H),

3.36 (s, 3H), 3.07 (m, 1H), 2.01 (m, 1H), 1.94 (m, 1H) ppm; MS m/e: 493.3 (M+H)*. Example 8 The synthetic procedure described above was adapted as described herein to make compound 1-8

below.

0

-"m NH N/ /0

F

1-8 (S)-I-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin

3-yl)-1H-1,2,4-triazole-3-carboxamide H NMR (CD 30D, 400 MHz) 8.55 (s, 1H), 7.37 (m, 2H), 7.08 (m, 3H), 6.72 (m, 2H), 5.43 (s, 2H), 4.98 (m, 1H), 4.49 (m, 1H), 4.26 (m, 1H), 3.83 (m, 2H), 3.70 (m, 2H), 3.64 (m, 4H), 3.37 (s, 3H), 2.01 (m, 2H) ppm; MS me: 495.3 (M+H)*. Example 9

The synthetic procedure described above was adapted as described herein to make compound 1-9 below.

NH'N\ N N N/O /0

1-9 (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3

yl)isoxazole-3-carboxamide H NMR (CD 30D, 400 MHz) 7.28 (m, 5H), 7.02 (d, J= 9.2 Hz, 1H), 6.69 (d, J = 2.8 Hz, IH), 6.65 (dd, J= 9.0,3.2 Hz, IH), 6.36 (s, IH), 4.97 (m, IH), 4.44 (m, IH), 4.29 (m, IH), 4.14 (s, 2H), 3.80 (m, 2H), 3.68 (m, 2H), 3.63 (m, 4H), 3.36 (s, 3H), 1.99 (m, 2H) ppm;MSm/e: 477.3 (M+H)*. Example 10 The synthetic procedure described above was adapted as described herein to make compound I-10 below.

NH N N N N~ /0O F

1-10 (S)-5-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin 3-yl)-1H-1,2,4-triazole-3-carboxamide H NMR (CD 30D, 400 MHz) 7.28 (m, 2H), 7.03 (m, 3H), 6.66 (m, 2H), 4.98 (m, 1H), 4.49 (m, 1H), 4.25 (m, 1H), 4.13 (s, 2H), 3.81 (m, 2H), 3.68 (m, 2H), 3.62 (m, 4H), 3.37 (s, 3H), 1.99 (m, 2H) ppm; MS me: 495.3 (M+H)-. Example 11 The synthetic procedure described above was adapted as described herein to make compound I-I1 below.

0 N

N/ 0 H~

F I-11 (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5 1 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide H NMR (CD 3 0D, 400 MHz) 7.27 (m, 2H), 7.03 (m, 3H), 6.43 (d, J= 2.4 Hz, 1H), 6.37 (dd, J= 8.8,2.8 Hz, 1H), 4.96 (m, 1H), 4.48 (m, 1H),

4.25 (m, 1H), 4.13 (s, 2H), 3.65 (m, 8H), 3.36 (s, 3H), 1.83 (m, 4H) ppm; MS m/e: 519.3 (M-H)-.

Example 12 The synthetic procedure described above was adapted as described herein to make compound 1-12 below.

0

NN

/ 0 H

1-12 (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H 1,2,4-triazole-3-carboxamide H NMR (CD 30D, 400 MHz) 7.26 (m, 4H), 7.02 (d, J= 9.2 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H), 6.66 (m, 1H), 4.99 (m, 1H), 4.49 (m, 1H), 4.25 (m, 1H), 4.14 (s, 2H), 3.82 (m, 2H), 3.69 (m,

2H), 3.62 (m, 4H), 3.37 (s, 3H), 1.99 (m, 2H) ppm; MS m/e: 475.3 (M-H)-.

Example 13 The synthetic procedure described above was adapted as described herein to make compound 1-13 below.

0

NH N N-O 0 0 /0

1-13 N-((3S)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin 3-yl)-5-benzylisoxazole-3-carboxamide H NMR (CD30D, 400 MHz) 7.32 (m, 5H), 7.04 (d, J= 8.8 Hz, 1H), 6.81 (d, J= 2.8 Hz, 1H), 6.76 (dd, J= 8.8, 2.8 Hz, 1H), 6.37 (s,1H), 4.94 (m,1H), 4.44 (m, 3H), 4.31 (m, 1H), 4.14 (s, 2H), 3.37 (m, 5H), 2.90 (m, 2H), 1.95 (m, 4H) ppm; MS me: 489.1 (M+H)*. Example 14 The synthetic procedure described above was adapted as described herein to make compound 1-14

below. 0

NH \

N/0

1-14 (S)-N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3 yl)-5-benzylisoxazole-3-carboxamide MS m/e: 502.3 (M+H)*. Other exemplary compounds are described below.

0

/0

(S)-5-benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5

tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

H nmr (400 MHz, CDCl 3) 8 8.08 (1H, d, J Hz, NH), 7.29-7.19 (5H, m, C 6H5 ),7.04 (1H, d, J 9.0 Hz, oxobenzoxazapineH-6), 6.74 (1H, dd, J 9.0, 2.5 Hz, oxobenzoxazapineH-7), 6.68 (1H, d, J 2.5 Hz, oxobenzoxazapineH-9), 5.06 (1H, dt, J 11.0, 7.5 Hz, oxobenzoxazapineH-3), 4.67 (1H, dd, J 10.0, 7.5 Hz, 1H of oxobenzoxazapineH-2), 4.21 (1H, dd, J 11.0, 10.0 Hz, 1H of oxobenzoxazapineH-2), 4.13 (2H, s, CH2 C6H5), 3.70, 3.68 (4H, 2d AB system, J 5.5 Hz, pyranH-2, H-6), 3.34 (3H, s, NCH 3), 3.20, 3.18 (4H, 2d AB system, J 5.5 Hz, piperidineH-2, H-6), 1.70-1.68 (4H, m, piperidineH-3, H-5), 1.56-1.53 (4H, m, pyranH-3, H-5); m/z: 531 [M+H]+ (found [M+H]+, 531.2711, C 29 H34 N6 04 requires [M+H]+ 531.2714).

o 0 N N N N 0

(S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR (400 MHz, Chloroform-d) 6 8.03 - 7.93 (m, 1H), 7.34 - 7.23 (m, 4H), 7.21 - 7.18 (m, 2H),

7.14 - 7.09 (m, 5H), 6.96 (br d, J= 8.8 Hz, 1H), 6.72 (br d, J= 8.9 Hz, 1H), 6.65 (br s, 1H), 4.94 (t, J= 9.2 Hz, 1H), 4.50 - 4.40 (m, 3H), 4.07 (t, J= 10.0 Hz, 1H), 3.94 (br s, 2H), 3.57 - 3.51 (m, 2H), 3.30 (s, 3H),

3.18 (t, J= 6.9 Hz, 2H), 2.86- 2.79 (m, 2H), 2.13 - 2.06 (m, 2H), 1.93 (t, J= 6.9 Hz, 2H), 1.54 - 1.50 (m, 2H); LRMS (M+H) m/z 620.5.

0 -IH NH N N N 0

(S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undecan-9-yl)-5-methyl-4-oxo-2,3,4,5

tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR (400 MHz, Chloroform-d) 68.00 - 7.83 (m, 1H), 7.31 - 7.17 (m, 6H), 7.06 - 7.04 (m, 5H), 6.91 (br d, J= 8.8 Hz, 1H), 6.66 (br d, J= 9.0 Hz, 1H), 6.59 (br s, 1H), 4.93 - 4.87 (m, 1H), 4.54 (br s, 2H), 4.38 (br s, 1H), 4.08 - 3.98 (m, 1H), 3.86 (br s, 2H), 3.45 - 3.39 (m, 2H), 3.24 (br s, 2H), 3.19 (br s, 3H), 2.95 - 2.88 (m, 2H), 2.37 - 2.30 (m, 2H), 1.80 - 1.77 (m, 4H), 1.61 - 1.58 (m, 2H); LRMS (M+H) m/z

634.5. Example 15 In this example, compounds of the disclosure were evaluated using a biochemical assay using the

ADP-GloTM technology. ADP-GloTM (Promega, Madison, WI, USA) reagents were thawed at ambient temperature. Kinase Detection Reagent was prepared by mixing kinase detection buffer with the lyophilized kinase detection substrate.

A 500m stock volume of 5X Reaction Kinase Buffer was made by mixing 1 0 0 0 pl of IM MgC 2 ,

500pl of IM Tris-HCL pH7.4,0.5mg/ml (25mg) of BSA, and 3475pl of distilled H 20. A 3ml 2X working stock volume of Reaction Kinase Buffer was made containing a final concentration of 100pM DTT and 4mM MnCl 2 .

Components of RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco, CA, USA) were

thawed on ice. Diluted RIPK1 was prepared in 1X Kinase Reaction Buffer (diluted from 2X buffer) to

31ng/well. A 166gM working stock ATP assay solution was prepared in 1X Kinase Reaction Buffer (diluted from 2X buffer).

Compounds were serially diluted in DMSO from 250uM in 4-fold dilutions then diluted 1:5 in 2X Reaction Buffer in a 96 well plate. 1.0ul of diluted compound was added to a 384 well plate in duplicate. 21 of diluted Active RIPK1 was added to 384 well plate (do not add to column) add 2X rxn buffer to column 1. AKT (Anaspec, Fremont, CA, USA) at 150nM was combined with ATP working stock at equal

volume and 2ul/well were added to the 384 well plate. The final reaction volume was 5.Opl.

The plate was quickly centrifuged and the reaction was incubated at 30°C for 30 minutes. Adding 5pl of ADP-GloTMterminated the reaction. The plate was quickly centrifuged and the reaction was incubated at room temperature for 40 minutes. Kinase Detection Reagent was then added and incubated at

room temperature for 30 minutes. The relative light unit (RLU) of kinase reaction was determined by luminescent (Luminescence 0.ls) using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA).

IC 5 ovalues obtained from this example are provided by Table 1. Table 1 Compound RIPi ADP-GloTM Kinase (C 50

) I-1 0.1977 1-2 0.0522 1-3 0.0374 1-4 0.0601 1-5 0.0678 1-6 0.0609 1-7 0.1075 1-8 0.2546 1-9 0.0392 1-10 0.3547 I-11 0.0394 1-12 0.0146 1-13 0.0145 1-14 0.4857 1-15 0.0425 1-16 0.2219 1-17 0.0404 1-18 0.088 1-19 0.0623 1-20 0.0482 1-21 0.0377 1-22 0.0236 1-23 0.0697 1-24 0.0745

Table 1 Compound RIPi ADP-GloTM Kinase(C 50

) 1-25 0.082 1-26 0.0164 1-27 0.0432

Example 16 In this example, U937 and L929 cells were exposed to compounds of the present disclosure and a cell necroptosis assay was conducted to evaluate the compounds' activity against human RIPI and murine RIP1. U937 and L929 cells were obtained from the American Type Culture Collection (Manassa,VA, USA). Both cells were maintained in logarithmic growth phase in complete RPMI 1640 media (Sigma, ST

Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA) at 37C with

5 % CO 2 . For necroptosis assay, L929 cells were plated for 18h in 100gL/well medium at 10K cells/well in

Costar 96-well black clear-bottom plates (Fisher Scientific, Hampton, NH, USA); U937 cells were plated on

the day of the assay in 50gL/well medium containing 60uM zVAD-fmk (Lonza, Basel, Switzerland) at 50K

cells/well. Medium from L929 cells were removed from the 96-well plates and replaced with 50 gL/well

new medium containing 40uM zVAD-fmk. Each compound of the present disclosure evaluated in this

example was serially diluted in DMSO from 2.5mM in 4-fold dilutions, and then diluted 1:125 in complete

medium. 50 gL/well 2x of the compound was then added to the cells in the plates. The cells were pre

incubated with the compound for 1 hour at 37C with 5 % CO 2 and before addition of 10 gL/well I1x TNFa

(Peprotech, Rocky Hill, NJ, USA) to give a final concentration of 2ng/mL for TNFa. The relative amount of

necroptosis cells was determined by luminescent using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA) and a CellTiter-Glo@ Luminescent Cell Viability Reagent Assay (Promega, Madison,

WI, USA) added per manufacturer instructions after 18 hours of TNFa stimulation at 37C with 5 % CO 2 .

Results from this example are summarized in Table 2. This example establishes that embodiments of the

compounds described herein have unexpectedly potent activity against human RIPI and murine RIP1, which

allows their assessment in in vivo mouse models of disease. These results are useful in determining safe and effective doses for humans.

Table 2 Compound L929-CTG-recovery, U937 Zvad TNF CTG L929, TNFa+zVAD Recovery, U937, TNFa+zVAD (IC50) (IC50 )

I-1 0.5562 0.0123 1-2 0.1244 0.004 1-3 0.2211 0.0007 1-4 0.2095 0.0032 1-5 0.3589 0.0035

Table 2 Compound L929-CTG-recovery, U937 Zvad TNF CTG L929, TNFa+zVAD Recovery, U937, TNFa+zVAD (IC50) (IC50

) 1-6 11.49 0.0273 1-7 2.493 0.0194 1-8 1.487 0.0089 1-9 4.128 0.0111 1-10 7.285 0.0275 I-11 0.4957 0.0121 1-12 5.167 0.0095 1-13 1.833 0.0063 1-14 21.34 0.2197 1-15 5.644 0.0695 1-16 5005 0.7679 1-17 1.862 0.0034 1-18 0.3418 0.003 1-19 0.9041 0.0065 1-20 4.626 0.0068 1-21 0.2673 0.0019 1-22 0.1422 0.0029 1-23 0.2354 0.0021 1-24 0.1044 0.0016 1-25 0.2007 0.0032 1-26 5.586 0.013 1-27 2.679 0.0211

Example 17 In this example, an acute hypothermia mouse model assay was used to evaluate the ability of

compounds disclosed herein to inhibit TNF-alpha induced hypothermia.

Female C57BL/6 mice are randomly grouped and weighed on Day-1. On the day of the study (Day 0), mice are administered vehicle or test article by oral gavage. Fifteen minutes after oral administration of

test agents, each mouse is administered an intraperitoneal (IP) injection of solution containing recombinant human tumor necrosis factor alpha (TNF-a, 25.0 pg) and zVAD-FMK (200 pg). Body temperature is measured at hour zero (before IP injections) and every hour via rectal probe temperature measuring device.

Three (3) hours after IP injections of TNF-a and zVAD/FMK, mice are euthanized by CO 2 asphyxiation and blood is collected via cardiac puncture. Serum and plasma are harvested for determination of cytokine and compound levels, respectively. Separate groups of mice (satellite mice) are included for the determination of compound levels in plasma at the time of administration of TNFa/zVAD-FMK. (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3 carboxamide (WO 2014/125444), having a structure as illustrated below, was used as a comparative compound and was examined using the same assay protocol. This comparative compound exhibited only

70% inhibition at 30 mg/kg. In comparison, compound 1-5 of the present disclosure achieved 81% inhibition at 15 mg/kg.

o -< N_ "NH N'

/ 0

Comparative Compound

In view of the many possible embodiments to which the principles of the present disclosure may be

applied, it should be recognized that the illustrated embodiments are only preferred examples and should not

be taken as limiting. Rather, the scope of the present disclosure is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims (21)

Claims:

1. A compound, having a formula 0 0 1 A O L (R ). 3 a N IR (W4) 2 O

or a pharmaceutically acceptable salt thereof, wherein: ring B is 5-membered heteroaryl; L is a Ci-ioaliphatic linker; R 1 is Ra or Rb wherein at least one R is an Rb that is -NRdRd wherein the two Rd groups together with the nitrogen bound thereto provide a non-aromatic C3-ioheterocyclic group that is optionally substituted with one or more R' and/or R9 groups, in which R9 is halogen, -Ci-ioaliphatic-Cs-ioaromatic, or =0; each of R2 and R3 independently are Ra; each R4 and each Ri ndependently are Ra or Rb; Ra is independently for each occurrence H, D, Ci-ioaliphatic, or Ci-iocycloaliphatic; Rb is independently, for each occurrence except for that of the said at least one R1, halogen or -NRdRd wherein (i) each Rd independently is R or Re; or (ii) two Rd groups together with the nitrogen bound thereto provide a C3 ioheterocyclic group; R° is independently for each occurrence -ORa, -NRa, Ci-6alkyl, Ci 6haloalkyl, C1-heteroalkyl, C3-cycloalkyl, or two Re groups join together to provide a C3-ioheterocyclic group with the Rb group to which the two R' groups are bound; m is 1 to 4; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein the compound has a structure satisfying a formula 0

N 3(R4) R R0

3. The compound of claim 1 or claim 2, wherein ring B has a structure

w, W satisfying a formula Ww , wherein at least one W is nitrogen, and each remaining W independently is selected from carbon, CH, oxygen, sulfur, nitrogen, or NH.

4. The compound of any one of claims 1-3, wherein ring B is a triazole selected from

N

N NN N HN N N ;or N

. or an oxazole selected from

N N /-N 0 '/// Ni3 or0

5. The compound of any one of claims 1-4, wherein R 5 is R, wherein Ra is Ci C4aliphatic, or R 5 is Rb, wherein Rb is halogen; and/or wherein R2 is Ra wherein Ra is Ci C4aliphatic and R3 is R, wherein Ra is hydrogen.

6. The compound of any one of claims 1-5, wherein R1 is Rb wherein Rb is -NRdRd wherein the two Rd groups together with the nitrogen bound thereto provide a substituted, non-aromatic C3-ioheterocyclic group, the substituents of which at least comprise two Re groups that join together to provide a second C3-oheterocyclic group, which provide a spirocyclic group or a bicyclic group.

7. The compound of claim 6, wherein the spirocyclic group comprises at least two rings, wherein a first ring and a second ring of the spirocyclic group have a different number of carbon atoms, a different number of heteroatoms, or both and wherein each ring of the spirocyclic group comprises a heteroatom in the ring.

8. The compound of claim 6 or 7, wherein the spirocyclic group comprises at least one oxygen atom and at least one nitrogen atom.

9. The compound of any one of claims 6-8, wherein the spirocyclic group comprises a first ring coupled to a carbon atom of the compound, the first ring having from 3 to 7 atoms and a second ring having from 3 to 7 atoms.

10. The compound of any one of claims 6-9, wherein the spirocyclic group comprises greater than 7 total atoms in the spirocyclic system.

11. The compound of any one of claims 6-10, wherein theC3-ioheterocyclic formed by the two Re groups and theC3-ioheterocyclic formed by the two Rd groups of R provide a bicyclic group and the bicyclic group comprises two or more heteroatoms in the bicyclic group.

12. The compound of claim 11, wherein the bicyclic group is a fused bicyclic group or a bridged bicyclic group and wherein the bicyclic group is attached to the ring A phenyl group of Formula I through a nitrogen atom of the bicyclic group.

13. The compound of any one of claims 1-12, wherein R1 is

HO 000 CI 0 N N) NC N"O

N N(R-NN R6 6 R -NNN\ N N

6 (JiN-N KN R6 NN

N ~ N N( 6 ) 6 -IR 6 \N N- R6r

NNR- (F

o0 0

H)1.r2 0;or

wherein each nindependently is aninteger ranging from 0to 4and R'independently is selected from hydrogen, aliphatic, aromatic, or heteroaliphatic.

14. The compound of any one of claims 1- 13, wherein the compound is selected from

0 0 0 0 H -NH -C\

HO 0C

I; 1-2;

0 0

0 0 -N"C\

N ~ N NN N I 0 N 0 /N 00

1-3; 1-4;

0 o 0

N-.N jN /0 H 1V/ o

H

1-5; 1-6;

0 0 N N- N

N 0

0 0 0

/ 0 F

1-7; 1-8;

0

0

N N- 0 NN - H a /dN N H

1-9; 1-12; 0 0

0 0

0NH -N I : NN o /0 H

0 F 0

I-li;1-16;

0 0 II

NH N

1-18;

0 0

NH I NH N 0 N ID N-.

0 H

J-,N AJN

NH NH N ,aN NN ~ -N..0 N

1-2 1; 1-22;

0o NH N N -NNH

1-23; 1-24;

0 00

0

1-25; 1-26; or

0 0 N

F NN N- N /N

1-27.

15. The compound of any one of claims 1-14, wherein the compound is

0 0

NH N

N N H IC 0

16. The compound of any one of claims 1-14, wherein the compound is 0

O --'''NH N N\

N NO N O

17. A pharmaceutical composition, comprising a compound according to any one of claims 1-16 and an excipient, a therapeutic agent, an adjuvant, or combinations thereof.

18. A method, comprising contacting a receptor-interacting protein-i (RIPi) kinase with a compound according to any one of claims 1-16, or the pharmaceutical composition of claim 17.

19. A method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of the compound of any one of claims 1-16, or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof; or (ii) a therapeutically effective amount of a pharmaceutical composition of claim 17; wherein the subject has, or is suspected of having or developing, the disease, wherein the disease is a disease involving a receptor-interacting protein-i (RIPi) kinase.

20. A method for making the compound of any one of claims 1-16, comprising: coupling a starting material having a Formula A with an R-containing reagent having a formula R1 -H, by combining the starting material and the R-containing reagent with a transition metal catalyst, a ligand component, and a solvent to form an R' functionalized product; deprotecting an amine group of the R-functionalized product to provide an amine compound; and forming an amide bond between the amine compound and an acid-containing coupling partner; wherein Formula A is

0 NHPG

(Xm N

Formula A;

the R1 -functionalized product has a structure satisfying Formula B

0 NHPG (Ri M 0 R2 O mR

Formula B;

and the acid-containing coupling partner has a structure satisfying Formula C

0 L R Cj Rj HO0 (Rh)n P

Formula C; and wherein X is a halogen or a triflate; PG is an amine protecting group; and each of ring B, L, R1 , R2, R4, R, m, n, and p are as recited for claim 1.

21. The method of claim 20, wherein the amide bond is formed by coupling the amine compound and the acid-containing coupling partner in the presence of propylphosphonic anhydride and diisopropylethylamine.

Rigel Pharmaceuticals, Inc.

Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON